HECT类泛素连接酶Smurf1活性调控、新功能及相关晶体结构研究
|
摘要
泛素-蛋白酶体途径是真核细胞内最为重要的蛋白质降解系统,它通过选择性清除细胞内错误折叠的以及特定环境下需要降解的蛋白质,对维持细胞正常的生理功能发挥至关重要的作用。泛素化修饰的过程是在泛素活化酶E1、泛素结合酶E2和泛素连接酶E3的顺序作用下介导泛素结合到底物蛋白,最后泛素链标记的底物蛋白被蛋白酶体识别并在其中降解。整个过程中E3决定了底物蛋白识别的特异性。E3主要分为两大类:RING类E3和HECT类E3。人们对HECT类E3的功能和活性调控认识主要来自于对Nedd4家族的研究。Nedd4家族E3在TGF-β、EGF、IGF、VEGF、SDF-1以及TNF-α等生长因子或细胞因子介导的信号通路中具有重要的调控作用。
作为Nedd4家族中的一员,Smurf1是在1999年筛选Smad相互作用蛋白时被发现可以降解TGF-β/BMP通路中的信号分子Smad1/5。后来又陆续发现了Smurf1的其它底物分子如RhoA、Runx2以及磷酸化形式的MEKK2等。Smurf1基因敲除和转基因小鼠骨表型分析都证明Smurf1在动物成体骨形成中发挥重要的负调控作用,强有力提示Smurf1是一个具有重要潜在价值的增强成骨细胞功能以治疗骨病的药物靶点。但是其调控分子,特别是可以调控其E3活性的调控分子一直没有被发现。
2005年Science杂志的一篇关于大规模相互作用蛋白筛选的研究报道酪蛋白激酶相互作用分子CKIP-1可能与Smurf1具有相互作用,但未做深入研究,这对相互作用的生化与生理功能均不清楚。CKIP-1首先被发现是酪蛋白激酶CK2的一个相互作用蛋白,本实验室在人胎肝转录组的研究中也曾克隆鉴定到此基因,成为国际上最早克隆此基因的实验室之一,并对其功能与调控开展了近十年的研究。基于分子和细胞水平的研究表明它在细胞凋亡、细胞分化、细胞骨架调控以及募集ATM和CK2到质膜定位中发挥作用,但是CKIP-1在动物整体水平上的体内生理功能一直不清楚。
我们对Smurf1与CKIP-1的相互作用及意义进行了深入的研究。首先证实CKIP-1可以特异的与Smurf1结合进而增强其E3活性,而与同家族的其它成员都没有相互作用。CKIP-1是第一个被发现的Smurf1活性增强因子。有意思的是,CKIP-1特异结合Smurf1分子中介导底物识别的两个WW结构域之间一段仅由15个氨基酸组成的连接区,而这段连接区在Smurf1与Nedd4家族其它成员之间存在序列差异,通过这种特异的靶向作用,CKIP-1上调Smurf1的E3活性、增强Smurf1与底物的结合力、进而促进Smurf1底物的泛素化降解。这是第一次揭示Smurf1的WW结构域之间的连接区也可以介导与其它蛋白的结合并在Smurf1的活性调控中发挥非常重要的功能。这种活性调控机制不同于已经发现的HECT类型E3的调控机制,因而代表了一种全新的泛素连接酶活性调节机制。在E3研究中长期存在的一个问题是为什么序列相近的E3成员具有不同的底物特异性和调控机制。我们的精细分析表明Smurf1 WW连接区的单个氨基酸的突变即可以导致E3结合调控分子及底物选择的改变,从而解释了为什么结构相似的E3如Smurf1和Smurf2,虽然序列高度同源但底物识别有所区别以及活性调控方式不同的问题。
在动物生理水平,CKIP-1基因敲除后小鼠骨量会随年龄增加而升高,成骨细胞功能增强,Smurf1的活性减弱。这不但是第一次真正阐明CKIP-1的生理功能,成为数量很少的成骨细胞功能调控成员中新的一员,更为重要的是证明CKIP-1对Smurf1的活性调控可以在生理水平发生而且对于骨形成具有重要的负调控作用,从而揭示了WW连接区介导的E3活性调控机制的真实性与重要性。CKIP-1与Smurf1的相互作用特别是介导结合的Smurf1的WW连接区成为具有重大筛选意义和应用前景的骨质疏松药物的潜在靶标。
为发现更多Smurf1的调节分子和底物,我们以Smurf1的WW结构域为诱饵通过酵母双杂交技术筛选到了TRAF4为其新的相互作用蛋白。TRAF4是TRAF家族成员。TRAF家族分子作为胞内接头蛋白,可以介导NF-κB和JNK-AP1通路的信号转导,进而参与骨代谢、先天性和获得性免疫、炎症应激响应等多种生物学过程。我们证实TRAF4是Smurf1的一个新的底物分子。当扩展到其他TRAF家族成员时,我们发现Smurf1对其它TRAF分子都可以进行泛素化修饰,而且逆转它们在NF-κB通路中的作用。我们的研究把Smurf1的底物范围扩展到TRAF家族,表明Smurf1在免疫和炎症反应中也具有调控作用,从而增加了人们对Smurf1新功能的认识。
Smurf1的C2结构域不但可以影响其自身泛素化,而且可以结合磷脂、从而对其定位和功能也具有重要的作用。我们对此结构域进行蛋白晶体结构解析并得到了精细的空间结构信息。Smurf1-C2由两组4个β片层形成的片层组和两端的loop组成,属于C2结构域家族中的class II类型。结构分析表明,Smurf1-C2结合磷脂的模式可能不同于PKC蛋白。对C2结构域的结构解析将有助于发现针对C2结构域并影响Smurf1整体分子功能的药物。
综上,我们的研究结果第一次证明Smurf1的WW结构域之间的连接区对于E3复合体的形成及E3活性的调节发挥重要功能,并揭示了CKIP-1是第一个增强Smurf1活性的重要辅助因子,而且CKIP-1对Smurf1的这种活性增强作用在动物整体水平得到了验证。我们进一步的研究把Smurf1的底物范围扩展到TRAF家族,表明Smurf1可能通过调控TRAF家族在免疫和炎症反应中发挥作用。对影响Smurf1功能的C2结构域进行了晶体结构解析,得到了其精细的空间结构信息,有助于设计特异性的针对Smurf1的小分子药物。
Ubiquitin-proteasome pathway plays crucial roles in cellular physiological function through selective removal of misfolded and specific proteins. Protein ubiquitination process is catalyzed sequentially by ubiquitin-activating enzyme E1, ubiquitin conjugating enzyme E2 and ubiquitin protein ligase E3 to label substrate proteins with ubiquitin chains which promote their degradation in the 26S proteasome. Ubiquitin ligase E3s determine the substrate specificity during this process. Two main E3 families are characterized: RING (really interesting new gene) finger-type E3s and HECT domain (homologous to E6AP C-terminus)-type E3s. Knowledge of HECT type E3s is mainly obtained from research on Nedd4 family which exerts important functions in various signaling pathways including those induced by TGF-β, EGF, IGF, VEGF, SDF-1, TNF-αand other growth factors or cytokines.
As a member of Nedd4 family, Smurf1 (Smad ubiquitination regulatory factor 1) was originally identified in 1999 as an E3 ligase of TGF-β/BMP pathway signaling molecules Smad1/5. RhoA, Runx2 and phosphorylated form of MEKK2 were subsequently found to be further substrates of Smurf1. Analysis of Smurf1 gene knockout and transgenic mice proved Smurf1 to be a negative regulator of bone formation, implicating that it might be a potential drug targets for bone diseases. However, whether and how its activity is regulated remains unclear.
In 2005, one Science paper reported CKIP-1 (caseine kinase 2 interacting protein-1) as an interacting partner of Smurf1 in a high throughput screening for protein-protein interactions in the TGF-β/BMP signaling network. However, the biochemical and physiological functions of the interaction between CKIP-1 and Smurf1 has not been investigated. CKIP-1 was originally found to be an interacting protein of casein kinase 2. Our laboratory identified the CKIP-1 gene firstly in the establishment of human fetal liver transcriptome and secondly investigated its function and regulation for about a decade. Studies based on the molecular and cellular levels revealed that CKIP-1 is involved in regulation of cell apoptosis, differentiation, cytoskeleton reorganization and recruitment of ATM and CK2 to the plasma membrane. However, its physiological role in vivo is still unknown due to lack of research on animal levels.
In this study, both the biochemical and physiological functions of the Smurf1-CKIP-1 interaction are thoroughly demonstrated. We first confirmed that CKIP-1 indeed specifically interacts with Smurf1 but not with other members of Nedd4 family, and enhances the E3 ligase activity of Smurf1. CKIP-1 functions as the first auxiliary factor to enhance the activation of Smurf1. Interestingly, CKIP-1 specifically targets the short linker region between the two WW domains of Smurf1 which mediate its interaction with substrates. The WW linker of Smurf1 consists of 15 amino acids and is distinct from that of other Nedd4 E3s. Through this manner, CKIP-1 enhances Smurf1 affinity with its substrates and promotes their ubiquitination and degradation. It is the first time to demonstrate that the short linker region between WW domains of Smurf1 could mediate the binding to its interacting protein; it is also the first time to show the importance of this short linker region for regulation of Smurf1 activity. This novel kind of regulatory mechanism is distinct from any known for HECT-type E3s. A long-standing question in understanding E3s is why closely related E3 members possess distinct substrate specificity and regulatory mechanism. Our results provide strong evidence that small differences in amino-acid sequence could accout for that specificity.
We recently established the CKIP-1 gene knockout mice model. Phenotype analysis showed that CKIP-1-deficient mice undergo an age-dependent bone mass increase as a result of accelerated osteogenesis and decreased Smurf1 activity. These findings confirm the importance of the WW domains linker in complex assembly, regulating activity of HECT-type E3s and in bone mass control in vivo. CKIP-1, like Smurf1, ATF4 and Shn3, belongs to the small group of factors that regulate potential osteoblast activity. As far as we know, this is also the first time to characterize the physiological function of CKIP-1. The linker region of Smurf1 and the CKIP-1-Smurf1 interaction may thus serve as therapeutic targets for the treatment of bone diseases such as osteoporosis.
In order to search for new substrates and/or regulators of Smurf1, we performed a yeast two-hybrid screening with the WW domains of Smurf1 as the bait and identified TRAF4 (TNF receptor associated factor 4) as one potential interacting partner. TRAF4 belongs to the TRAF family which functions as intracellular signaling adaptors to mediate NF-κB and JNK-AP-1 pathways and participate in bone metabolism, native and adaptive immunity and inflammation. Our further research showed that TRAF4 is a new substrate of Smurf1. When extended to other TRAF family members, we found that Smurf1 could promote their ubiquitination and reverse their negative or positive roles in NF-κB transcription activation. These results indicate novel functions of Smurf1 in immunity and inflammatory responses through targeting TRAF family members as its ubiquitination substrates.
The C2 domain of Smurf1 not only affects its self-ubiquitination but also is important for its localization and function. Based on the crystal structure information of C2 We demonstrate that Smurf1-C2 belongs to classⅡtype and its molecular potential especially the regions for phospho-lipid binding is different from classical C2 domain of PKC. The knowledge of Smurf1-C2 structure will contribute to develop ment of clinical drugs that target C2 domain and affect functions of Smurf1.
Taken together, we demonstrated for the first time that the short linker region between WW domains of Smurf1 exerts critical functions in complex assembly and in E3 activity regulation. CKIP-1 functions as the first auxiliary factor of Smurf1 and the interaction between CKIP-1 and Smurf1 is critical in bone mass control as indicated by gene knockout mouse models. Our research extends substrates of Smurf1 to TRAF family and indicates novel functions of Smurf1 in immunity and inflammation. Furthermore, we obtained the crystal structure of the C2 domain of Smurf1 which is beneficial for potential drug design.
作为Nedd4家族中的一员,Smurf1是在1999年筛选Smad相互作用蛋白时被发现可以降解TGF-β/BMP通路中的信号分子Smad1/5。后来又陆续发现了Smurf1的其它底物分子如RhoA、Runx2以及磷酸化形式的MEKK2等。Smurf1基因敲除和转基因小鼠骨表型分析都证明Smurf1在动物成体骨形成中发挥重要的负调控作用,强有力提示Smurf1是一个具有重要潜在价值的增强成骨细胞功能以治疗骨病的药物靶点。但是其调控分子,特别是可以调控其E3活性的调控分子一直没有被发现。
2005年Science杂志的一篇关于大规模相互作用蛋白筛选的研究报道酪蛋白激酶相互作用分子CKIP-1可能与Smurf1具有相互作用,但未做深入研究,这对相互作用的生化与生理功能均不清楚。CKIP-1首先被发现是酪蛋白激酶CK2的一个相互作用蛋白,本实验室在人胎肝转录组的研究中也曾克隆鉴定到此基因,成为国际上最早克隆此基因的实验室之一,并对其功能与调控开展了近十年的研究。基于分子和细胞水平的研究表明它在细胞凋亡、细胞分化、细胞骨架调控以及募集ATM和CK2到质膜定位中发挥作用,但是CKIP-1在动物整体水平上的体内生理功能一直不清楚。
我们对Smurf1与CKIP-1的相互作用及意义进行了深入的研究。首先证实CKIP-1可以特异的与Smurf1结合进而增强其E3活性,而与同家族的其它成员都没有相互作用。CKIP-1是第一个被发现的Smurf1活性增强因子。有意思的是,CKIP-1特异结合Smurf1分子中介导底物识别的两个WW结构域之间一段仅由15个氨基酸组成的连接区,而这段连接区在Smurf1与Nedd4家族其它成员之间存在序列差异,通过这种特异的靶向作用,CKIP-1上调Smurf1的E3活性、增强Smurf1与底物的结合力、进而促进Smurf1底物的泛素化降解。这是第一次揭示Smurf1的WW结构域之间的连接区也可以介导与其它蛋白的结合并在Smurf1的活性调控中发挥非常重要的功能。这种活性调控机制不同于已经发现的HECT类型E3的调控机制,因而代表了一种全新的泛素连接酶活性调节机制。在E3研究中长期存在的一个问题是为什么序列相近的E3成员具有不同的底物特异性和调控机制。我们的精细分析表明Smurf1 WW连接区的单个氨基酸的突变即可以导致E3结合调控分子及底物选择的改变,从而解释了为什么结构相似的E3如Smurf1和Smurf2,虽然序列高度同源但底物识别有所区别以及活性调控方式不同的问题。
在动物生理水平,CKIP-1基因敲除后小鼠骨量会随年龄增加而升高,成骨细胞功能增强,Smurf1的活性减弱。这不但是第一次真正阐明CKIP-1的生理功能,成为数量很少的成骨细胞功能调控成员中新的一员,更为重要的是证明CKIP-1对Smurf1的活性调控可以在生理水平发生而且对于骨形成具有重要的负调控作用,从而揭示了WW连接区介导的E3活性调控机制的真实性与重要性。CKIP-1与Smurf1的相互作用特别是介导结合的Smurf1的WW连接区成为具有重大筛选意义和应用前景的骨质疏松药物的潜在靶标。
为发现更多Smurf1的调节分子和底物,我们以Smurf1的WW结构域为诱饵通过酵母双杂交技术筛选到了TRAF4为其新的相互作用蛋白。TRAF4是TRAF家族成员。TRAF家族分子作为胞内接头蛋白,可以介导NF-κB和JNK-AP1通路的信号转导,进而参与骨代谢、先天性和获得性免疫、炎症应激响应等多种生物学过程。我们证实TRAF4是Smurf1的一个新的底物分子。当扩展到其他TRAF家族成员时,我们发现Smurf1对其它TRAF分子都可以进行泛素化修饰,而且逆转它们在NF-κB通路中的作用。我们的研究把Smurf1的底物范围扩展到TRAF家族,表明Smurf1在免疫和炎症反应中也具有调控作用,从而增加了人们对Smurf1新功能的认识。
Smurf1的C2结构域不但可以影响其自身泛素化,而且可以结合磷脂、从而对其定位和功能也具有重要的作用。我们对此结构域进行蛋白晶体结构解析并得到了精细的空间结构信息。Smurf1-C2由两组4个β片层形成的片层组和两端的loop组成,属于C2结构域家族中的class II类型。结构分析表明,Smurf1-C2结合磷脂的模式可能不同于PKC蛋白。对C2结构域的结构解析将有助于发现针对C2结构域并影响Smurf1整体分子功能的药物。
综上,我们的研究结果第一次证明Smurf1的WW结构域之间的连接区对于E3复合体的形成及E3活性的调节发挥重要功能,并揭示了CKIP-1是第一个增强Smurf1活性的重要辅助因子,而且CKIP-1对Smurf1的这种活性增强作用在动物整体水平得到了验证。我们进一步的研究把Smurf1的底物范围扩展到TRAF家族,表明Smurf1可能通过调控TRAF家族在免疫和炎症反应中发挥作用。对影响Smurf1功能的C2结构域进行了晶体结构解析,得到了其精细的空间结构信息,有助于设计特异性的针对Smurf1的小分子药物。
Ubiquitin-proteasome pathway plays crucial roles in cellular physiological function through selective removal of misfolded and specific proteins. Protein ubiquitination process is catalyzed sequentially by ubiquitin-activating enzyme E1, ubiquitin conjugating enzyme E2 and ubiquitin protein ligase E3 to label substrate proteins with ubiquitin chains which promote their degradation in the 26S proteasome. Ubiquitin ligase E3s determine the substrate specificity during this process. Two main E3 families are characterized: RING (really interesting new gene) finger-type E3s and HECT domain (homologous to E6AP C-terminus)-type E3s. Knowledge of HECT type E3s is mainly obtained from research on Nedd4 family which exerts important functions in various signaling pathways including those induced by TGF-β, EGF, IGF, VEGF, SDF-1, TNF-αand other growth factors or cytokines.
As a member of Nedd4 family, Smurf1 (Smad ubiquitination regulatory factor 1) was originally identified in 1999 as an E3 ligase of TGF-β/BMP pathway signaling molecules Smad1/5. RhoA, Runx2 and phosphorylated form of MEKK2 were subsequently found to be further substrates of Smurf1. Analysis of Smurf1 gene knockout and transgenic mice proved Smurf1 to be a negative regulator of bone formation, implicating that it might be a potential drug targets for bone diseases. However, whether and how its activity is regulated remains unclear.
In 2005, one Science paper reported CKIP-1 (caseine kinase 2 interacting protein-1) as an interacting partner of Smurf1 in a high throughput screening for protein-protein interactions in the TGF-β/BMP signaling network. However, the biochemical and physiological functions of the interaction between CKIP-1 and Smurf1 has not been investigated. CKIP-1 was originally found to be an interacting protein of casein kinase 2. Our laboratory identified the CKIP-1 gene firstly in the establishment of human fetal liver transcriptome and secondly investigated its function and regulation for about a decade. Studies based on the molecular and cellular levels revealed that CKIP-1 is involved in regulation of cell apoptosis, differentiation, cytoskeleton reorganization and recruitment of ATM and CK2 to the plasma membrane. However, its physiological role in vivo is still unknown due to lack of research on animal levels.
In this study, both the biochemical and physiological functions of the Smurf1-CKIP-1 interaction are thoroughly demonstrated. We first confirmed that CKIP-1 indeed specifically interacts with Smurf1 but not with other members of Nedd4 family, and enhances the E3 ligase activity of Smurf1. CKIP-1 functions as the first auxiliary factor to enhance the activation of Smurf1. Interestingly, CKIP-1 specifically targets the short linker region between the two WW domains of Smurf1 which mediate its interaction with substrates. The WW linker of Smurf1 consists of 15 amino acids and is distinct from that of other Nedd4 E3s. Through this manner, CKIP-1 enhances Smurf1 affinity with its substrates and promotes their ubiquitination and degradation. It is the first time to demonstrate that the short linker region between WW domains of Smurf1 could mediate the binding to its interacting protein; it is also the first time to show the importance of this short linker region for regulation of Smurf1 activity. This novel kind of regulatory mechanism is distinct from any known for HECT-type E3s. A long-standing question in understanding E3s is why closely related E3 members possess distinct substrate specificity and regulatory mechanism. Our results provide strong evidence that small differences in amino-acid sequence could accout for that specificity.
We recently established the CKIP-1 gene knockout mice model. Phenotype analysis showed that CKIP-1-deficient mice undergo an age-dependent bone mass increase as a result of accelerated osteogenesis and decreased Smurf1 activity. These findings confirm the importance of the WW domains linker in complex assembly, regulating activity of HECT-type E3s and in bone mass control in vivo. CKIP-1, like Smurf1, ATF4 and Shn3, belongs to the small group of factors that regulate potential osteoblast activity. As far as we know, this is also the first time to characterize the physiological function of CKIP-1. The linker region of Smurf1 and the CKIP-1-Smurf1 interaction may thus serve as therapeutic targets for the treatment of bone diseases such as osteoporosis.
In order to search for new substrates and/or regulators of Smurf1, we performed a yeast two-hybrid screening with the WW domains of Smurf1 as the bait and identified TRAF4 (TNF receptor associated factor 4) as one potential interacting partner. TRAF4 belongs to the TRAF family which functions as intracellular signaling adaptors to mediate NF-κB and JNK-AP-1 pathways and participate in bone metabolism, native and adaptive immunity and inflammation. Our further research showed that TRAF4 is a new substrate of Smurf1. When extended to other TRAF family members, we found that Smurf1 could promote their ubiquitination and reverse their negative or positive roles in NF-κB transcription activation. These results indicate novel functions of Smurf1 in immunity and inflammatory responses through targeting TRAF family members as its ubiquitination substrates.
The C2 domain of Smurf1 not only affects its self-ubiquitination but also is important for its localization and function. Based on the crystal structure information of C2 We demonstrate that Smurf1-C2 belongs to classⅡtype and its molecular potential especially the regions for phospho-lipid binding is different from classical C2 domain of PKC. The knowledge of Smurf1-C2 structure will contribute to develop ment of clinical drugs that target C2 domain and affect functions of Smurf1.
Taken together, we demonstrated for the first time that the short linker region between WW domains of Smurf1 exerts critical functions in complex assembly and in E3 activity regulation. CKIP-1 functions as the first auxiliary factor of Smurf1 and the interaction between CKIP-1 and Smurf1 is critical in bone mass control as indicated by gene knockout mouse models. Our research extends substrates of Smurf1 to TRAF family and indicates novel functions of Smurf1 in immunity and inflammation. Furthermore, we obtained the crystal structure of the C2 domain of Smurf1 which is beneficial for potential drug design.
引文
[1] Simpson MV. The release of labeled amino acids from the proteins of rat liver slices, J Biol Chem, 1953, 201: 143-54
[2] Etlinger JD, Goldberg AL. A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes, Proc Natl Acad Sci USA, 1977, 74(1):54-8
[3] Hershko A, Tomkins GM. Studies on the degradation of tyrosine aminotransferase in hepatoma cells in culture. Influence of the composition of the medium and adenosine triphosphate dependence, J Biol Chem, 1971, 246(3):710-4
[4] Ciehanover A, Hod Y, Hershko A. A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes, Biochem Biophys Res Commun, 1978 , 81(4):1100-5
[5] Hershko A, Ciechanover A, Heller H, et al. Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis, Proc Natl Acad Sci USA, 1980, 77(4):1783-6
[6] Ciechanover A, Heller H, Elias S, et al. ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation, Proc Natl Acad Sci USA. 1980 ,77(3):1365-8
[7] Wilkinson KD, Urban MK, Haas AL. Ubiquitin is the ATP-dependent proteolysis factor I of rabbit reticulocytes, J Biol Chem, 1980, 255(16):7529-32
[8] Ciechanover A, Elias S, Heller H, et al. "Covalent affinity" purification of ubiquitin-activating enzyme, J Biol Chem, 1982, 257(5): 2537-42
[9] Hershko A, Heller H, Elias S, et al. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown, J Biol Chem, 1983, 258(13): 8206-14
[10] Hough R, Pratt G, Rechsteiner M. Ubiquitin-lysozyme conjugates: Identification and characterization of an ATP-dependent protease from rabbit reticulocyte lysates, J Biol Chem, 1986, 261(5): 2400-8
[11] Hough R, Pratt G, Rechsteiner M. Purification of two high molecular weight proteases from rabbit reticulocyte lysate, J Biol Chem, 1987, 262(17): 8303-13
[12] Hilt W, Wolf D H. Proteasomes: The World of Regulatory Proteolysis, LANDESBIOSCIENCE PUBLISHERS, 2001, 301
[13] Ciechanover A. The ubiquitin-proteasome pathway: on protein death and cell life, EMBO J, 1998, 17(24): 7151-60
[14] Ciechanover A, Iwai K. The ubiquitin system: from basic mechanisms to the patient bed, IUBMB Life, 2004, 56: 193-201
[15] Hoeller D, Hecker CM and Dikic I. Ubiquitin and ubiquitin-like proteins in cancer pathogenesis, Nat Rev Cancer, 2006, 6: 776-88
[16] Cook WJ, Bugg CE, Vijay-Kumar S. Structure of ubiquitin refined at 1.8 ? resolution, J Mol Biol, 1987, 194(3): 531-44
[17] Peoski MD, Deshaies RJ. Function and regulation of culling-RING ubiquitin ligases, Nat Rev Mol Cell Biol, 2005, 6(1): 9-20
[18] Zheng N.A closer look of the HECTic ubiquitin ligases, Structure, 2003, 11(1): 5-6
[19] Huang L, Kinnucan E, Wang G, et al. Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade, Science, 1999, 286(5443): 1321-6
[20] Verdecia MA, Joazeiro CA, Wells NJ. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase, Mol Cell, 2003, 11: 249–59
[21] Ogunjimi AA, Briant DJ, Pece-Barbara N, et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain, Mol Cell, 2005, 19: 297–308
[22] Kamadurai HB, Souphron J, Scott DC, et al. Insights into ubiquitin transfer cascades from a structure of a UbcH5B approximately ubiquitin-HECT (NEDD4L) complex, Mol Cell, 2009, 36: 1095-1102
[23] Pandya RK, Partridge JR, Love KR, et al. A structural element within the HUWE1 HECT domain modulates self-ubiquitination and substrate ubiquitination activities, J Biol Chem, 2010, 285(8): 5664-73
[24] ROlfe M,Beer-Romero P,Glass S,et a1.Reconstitution of p53-ubiquitinylation reactions from purified components:the role of human ubiquitin-conjugating enzyme UBC4 and E6 associated protein (E6AP), Proc Natl Acad Sci USA, 1995, 92(8): 3264-8
[25] Shearwin-Whyatt L, Dalton HE, Foot N, et a1. Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins, Bioessays,2006, 28: 617–28
[26] Ingham RJ, Gish G, Pawson T. The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture, Oncogene, 2004, 23(11): 1972-84
[27] Rotin D, Staub O, Haguenauer-Tsapis R. Ubiquitination and endocytosis of plasma membrane proteins: role of Nedd4/Rsp5p family of ubiquitin-protein ligases, J Membr Biol, 2000, 176(1): 1-17
[28] Tamai KK, Shimoda C. The novel HECT-type ubiquitin-protein ligase Pub2p shares partially overlapping function with Pub1p in Schizosaccharomyces pombe, J Cell Sci, 2002, 115(9): 1847-57
[29] Huang K, Johnson KD, Petcherski AG, et al. A HECT domain ubiquitin ligase closely related to the mammalian protein WWP1 is essential for Caenorhabditis elegans embryogenesis, Gene, 2000, 252(1-2): 137-45
[30] Myat A, Henry P, McCabe V, et al. Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor, Neuron, 2002, 35(3): 447-59
[31] Podos SD, Hanson KK, Wang YC, et al. The DSmurf ubiquitin-protein ligase restricts BMP signaling spatially and temporally during Drosophila embryogenesis, Dev Cell, 2001, 1(4): 567-78
[32] Chen C, Matesic LE. The Nedd4-like family of E3 ubiquitin ligases and cancer, Cancer Metastasis Rev, 2007, 26(3-4): 587-604
[33] Kamynina E, Tauxe C, Staub O. Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation, Am J Physiol Renal Physiol, 2001, 281(3): 469-77
[34] Myat A, Henry P, McCabe V, et al. Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor, Neuron, 2002, 35(3): 447-59
[35] Chen S, BhargavaA, Mastroberardino L, et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk, Proc Natl Acad Sci USA, 1999, 96: 2514-9
[36] Snyder PM, Olson DR, Thomas BC. Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel, J Biol Chem, 2002, 277(1): 5-8
[37] Ichimura T, Yamamura H, Sasamoto K, et al. 14-3-3 proteins modulate theexpression of epithelial Na+ channels by phosphorylation -dependent interaction with Nedd4-2 ubiquitin ligase, J Biol Chem, 2005, 280(13): 13187-94
[38] Bhalla V, DaidiéD, Li H, et al. Serum- and glucocorticoid-regulated kinase 1 regulates ubiquitin ligase neural precursor cell-expressed developmentally down-regulated protein 4-2 by inducing interaction with 14-3-3, Mol Endocrinol, 2005, 19(12): 3073-84
[39] Snyder PM, Olson DR, Kabra R, et al. cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2, J Biol Chem, 2004, 279(44): 45753-8
[40] Lee IH, Dinudom A, Sanchez-Perez A, et al. Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2, J Biol Chem, 2007, 282(41): 29866-73
[41] Edinger RS, Lebowitz J, Li H, et al. Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2, J Biol Chem, 2009, 284(1): 150-7
[42] Bhalla V, Oyster NM, Fitch AC, et al. AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2, J Biol Chem, 2006, 281(36): 26159-69
[43] Bhalla V, Daidie D, Li H , et al. Serum and glucocorticoid regulated kinase 1 regulates ubiquitin ligase neural precursor cell expressed, developmentally down regulated protein 4-2 by interaction with 14-3-3, Mol Endocrinol, 2005, 19: 3073-84
[44] Gao M, Labuda T, Xia Y, et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch, Science, 2004, 306: 271–5
[45] Tanoue T, Maeda R, Adachi M, et al. Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions, EMBO J, 2001, 20: 466–79
[46] Gallagher E, Gao M, Liu YC, et al. Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change, Proc Natl Acad Sci USA, 2006, 103: 1717–22.
[47] Yang C, Zhou W, Jeon MS, et al. Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation, Mol Cell, 2006, 21(1): 135-41
[48] Nuber U, Schwarz SE, Scheffner M. The ubiquitin-protein ligase E6-associated protein (E6-AP) serves as its own Substrate, Eur J Biochem, 1998, 254, 643-9
[49] Oberst A, Malatesta M, Aqeilan RI, et al. The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch, Proc Natl Acad Sci USA, 2007, 104: 11280-5
[50] Wiesner S, Ogunjimi AA, Wang HR, et al. Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain, Cell, 2007, 130(4): 651-62
[51] Kavsak P, Rasmussen RK, Causing CG, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation, Mol Cell, 2000, 6(6): 1365-75
[52] Ebisawa T, Fukuchi M, Murakami G, et al. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation, J Biol Chem, 2001, 276(16): 12477-80
[53] Plant PJ, Lafont F, Lecat S, et al. Apical membrane targeting of Nedd4 is mediated by an association of Its C2 domain with Annexin XIIIb, J Cell Biol, 2000, 149: 1473-84
[54] Kitching R, Wong MJ, Koehler D, et al. The RING-H2 protein RNF11 is differentially expressed in breast tumors and interacts with HECT-type E3 ligases, Biochim Biophys Acta, 2003, 1639(2): 104-12
[55] Li H, Seth A. An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein, Oncogene, 2004, 23(10): 1801-8
[56] Zhao M, Qiao M, Oyajobi B, et al. E3 ubiquitin ligase Smurf1 mediates core-binding factorα1/Runx2 degradation and plays a specific role in osteoblast differentiation, J Biol Chem, 2003, 278 (30): 27939-44
[57] Shen R, Chen M, Wang YJ, et al. Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation, J Biol Chem, 2006, 281(6): 3569-76
[58] Jones DC, Wein MN, Oukka M, et al. Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3, Science, 2006, 312: 1223-7
[59] Hettema EH, Valdez-Taubas J, Pelham HR. Bsd2 binds the ubiquitin ligase Rsp5 and mediates the ubiquitination of transmembrane proteins, EMBO J, 2004, 23: 1279-88
[60] Harvey KF, Shearwin-Whyatt LM, Fotia A, et al. N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associatedprotein, J Biol Chem, 2002, 277: 9307–17
[61] Oliver PM, Cao X, Worthen GS, et al. Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation, Immunity, 2006, 25(6): 929-40
[62] Sangadala S, Boden SD, Viggeswarapu M, et al. LIM mineralization protein-1 potentiates bone morphogenetic protein responsiveness via a novel interaction with Smurf1 resulting in decreased ubiquitination of Smads, J Biol Chem, 2006, 281(25): 17212-9
[63] Kee Y, Lyon N, Huibregtse JM. The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme, EMBO J, 2005, 24(13): 2414-24
[64] Mouchantaf R, Azakir BA, McPherson PS, et al. The ubiquitin ligase itch is auto-ubiquitylated in vivo and in vitro but is protected from degradation by interacting with the deubiquitylating enzyme FAM/USP9X, J Biol Chem, 2006, 281(50): 38738-47
[65] Flasza M, Gorman P, Roylance R. Alternative splicing determines the domain structure of WWP1, a Nedd4 family protein, Biochem Biophy Res Commun, 2002, 290: 431–7
[66] Qi H, Grenier J, Fournier A, et al. Androgens differentially regulate the expression of NEDD4L transcripts in LNCaP human prostate cancer cells, Mol Cell Endocrin, 2003, 210: 51–62
[67] Ohashi N, Yamamoto T, Uchida C, et al. Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta, FEBS Lett, 2005, 579: 2557-63
[68] Kaneki H, Guo R, Chen D, et al. Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts, J Biol Chem, 2006, 281: 4326–33
[69] Judge AR, Koncarevic A, Hunter RB, et al. Role for IkappaBalpha, but not c-Rel, in skeletal muscle atrophy, Am J Physiol, 2007, 292: C372–82
[70] Zhang H, Cohen SN. Smurf2 up-regulation activates telomere-dependent senescence, Genes Dev, 2004, 18: 3028–40
[71] Gu Z, Rubin MA, Yang Y, et al. Reg IV: A promising marker of hormone refractory metastatic prostate cancer, Clin Cancer Res, 2005, 11: 2237–43
[72] Imhof MO, McDonnell D P. Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by humanprogesterone and glucocorticoid receptors, Mol Cell Biol, 1996,16: 2594–2605
[73] Rossi M, De Laurenzi V, Munarriz E, et al. The ubiquitin-protein ligase Itch regulates p73 stability, EMBO J, 2005, 24: 836–48
[74] Laine A , Ronai Z. Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1, Oncogene, 2007, 26:1477–83
[75] Yang Y, Kitagaki J, Wang H, et al. Targeting the ubiquitin-proteasome system for cancer therapy, Cancer Sci, 2009, 100 (1): 24–8
[76] Eldridge AG , O’Brien T. Therapeutic strategies within the ubiquitin proteasome system, Cell Death Differ, 2010, 17: 4–13
[77] Bernassola F, Karin M, Ciechanover A, et al. The HECT family of E3 ubiquitin ligases: multiple players in cancer development, Cancer Cell, 2008, 14: 10-21
[78] Rotin D, Kumar S. Physiological functions of the HECT family of ubiquitin ligases, Nat Rev Mol Cell Biol, 2009, 10: 398-409
[79] Martin S, Olivier S. HECT E3s and human disease, BMC Biochemistry, 2007, 8 (Suppl 1): S6
[80] Kee Y, Huibregtse JM. Regulation of catalytic activities of HECT ubiquitin ligase, Biochem Biophyl Res Commun, 2007, 354: 329–33
[81] Lee NK, Lee SY. Modulation of Life and Death by the Tumor Necrosis Factor Receptor- Associated Factors (TRAFs), J Biochem Mol Biol, 2002, 35(1): 61-6
[82] Bishop GA, Moore CR, Xie P et al. TRAF proteins in CD40 signaling, Adv Exp Med Biol, 2007, 597:131–51
[83] Chung J, Park YC, Ye H et al. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci, 2002, 115: 679–88
[84] Rothe M,Wong SC,Henzel WJ, et al. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor, Cel1, 1994, 78: 68l-92
[85] Cao ZD,Xiong J,Takeuchi M, et a1.TRAF6 is a signal transducer for Interleukin-1, Nature, 1996, 383: 443-6
[86] Malinin NL,Boldin MP,Kovalenko AV, et a1.MAP3K-related kinase involved in NF-κB induction by TNF-α,CD95 and IL-1, Nature, 1997, 385: 540-4
[87] Cheng G, Baltimore D.TANK, a co-inducer with TRAF2 of TNF and CD40L-mediated NF-κB activation, Genes Dev, 1996,10: 963-73
[88] Song HY , Regnier CH , Kirschning CJ, et a1 . Tumor necrosisfactor(TNF)-mediated kinase cascades:Bifurcation of nuclear factor-κB and c-jun N-terminal kinase(JNK/SAPK)pathways at TNF receptor associated factor 2, Proc Natl Acad Sci USA, 1997, 94: 9792-6
[89] Rothe M,Pan MG,Henzel WJ, et a1.The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins, Cell, 1995, 83: 1243-52
[90] Park YC,Burkitt V,Villa AR,et a1.Structural basis for self-association and receptor recognition of human TRAF2, Nature, 1999, 398: 533-8
[91] Freemont PS.RING for destruction? Curr Bio1, 2000,10:R84-87
[92] Dadgostar H,Cheng G.An intact zinc ring finger is required for tumor necrosis factor receptor associated factor mediated nuclear factor-κB activation but is dispensable for c-Jun N-terminal kinase signaling, J Biol Chem, 1998, 273: 24775-80
[93] Pineda G,Ea CK,Chen ZJ.Ubiquitination and TRAF signaling.Adv Exp Med Bio1, 2007, 597: 80-92
[94] Chen ZJ. Ubiquitin signalling in the NF-κB pathway, Nat Cell Boil, 2005, 7:758-766
[95] Wang C. Deng L, Hong M, et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK, Nature, 2001, 412: 346–51
[96] Kanayama A, Seth RB, Sun L, et al. TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains, Mol Cell, 2004 15: 535–48
[97] Shi CS and Kehrl JH. Tumor necrosis factor (TNF)-induced germinal center kinase related (GCKR) and stress-activated protein kinase (SAPK) activation depends upon the E2/E3 complex Ubc13-Uev1A/TNF receptor-associated factor 2 (TRAF2), J Biol Chem, 2003, 278: 15429–34
[98] Habelhah H, Takahashi S, Cho SG, et al. Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF-κB, EMBO J, 2004, 23: 322–32
[99] Lee TH, Shank J, Cusson N, et al. The kinase activity of Rip1 is not required for tumor necrosis factor-alpha-induced IκB kinase or p38 MAP kinase activation or for the ubiquitination of Rip1 by Traf2, J Biol Chem, 2004, 279: 33185–191
[100] Hofmann RM, Pickart CM. Noncanonical MMS2-encoded ubiquitin conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair, Cell, 1999, 96: 645–53
[101] Jang H D, Chung YM, Baik JY, et al. Caspase-cleaved TRAF1 negatively regulates the antiapoptotic signals of TRAF2 during TNF-induced cell death, Biochem Biophy Res Commun, 2001, 281: 499-505
[102] Zheng C, Kabaleeswaran V, Wang Y, et al. Crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes: affinity, specificity, and regulation , Mol Cell, 2010, 38: 101-13
[103] Tsitsikov EN, Laouin D, Dunn I F, et al. TRAF1 is a negative regulator of TNF signaling: enhanced TNF signaling in TRAF1-deficient mice, Immunity, 2001, 15: 647-57
[104] Yeh W C, Shahinian A, Speiser D, et al. Early lethality, functional NF-κB activation and increased sensitivity to TNF-induced cell death in TRAF2 deficient mice, Immunity, 1997, 7: 715-25
[105] Hauer J, Püschner S, Ramakrishnan P, et al. TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs, Proc Natl Acad Sci USA, 2005, 102: 2874-9
[106] Kedinger V, Alpy F, Tomasetto C, et al. Spatial and temporal distribution of the traf4 genes during zebrafish development, Gene Expr Patterns, 2005, 5(4): 545-52
[107] Tada K, Okazaki T, Sakon S, et al. Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death, J Biol Chem, 2001, 276(39): 36530-4
[108] Chung JY, Lu M, Yin Q, et al. Molecular basis for the unique specificity of TRAF6, Adv Exp Med Biol, 2007, 597: 122-30
[109] Lee NK, Choi YG, Baik JY, et al. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation, Blood, 2005, 106(3): 852-9
[110] Ohazama A, Courtney JM, Tucker AS, et al. Traf6 is essential for murine tooth cusp morphogenesis, Dev Dyn, 2004, 229(1):131-5
[111] Zhu H, Kavsak P, Abdollah S, et al. SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation, Nature, 1999, 400: 687-93
[112] Tajima Y, GotoK, Yoshida M, et al. Chromosomal Region Maintenance 1 (CRM1)-dependent Nuclear Export of Smad Ubiquitin Regulatory Factor 1 (Smurf1) Is Essential for Negative Regulation of Transforming Growth Factor-Signaling by Smad7, J Biol Chem, 2003, 278(12): 10716–21
[113] Suzuki C, Murakami G, Fukuchi M,et al. Smurf1 Regulates the Inhibitory Activity of Smad7 by Targeting Smad7 to the Plasma Membrane,J Biol Chem, 2002,277(42): 39919–25
[114] Bellido T, Ali AA, Plotkin LI, et al. Proteasomal Degradation of Runx2 Shortens Parathyroid Hormone-induced Anti-apoptotic Signaling in Osteoblasts, 2003, J Biol Chem, 278(50): 50259–72
[115] Wang HR, Zhang Y, Ozdamar B, et al. Regulation of cell polarity and protrusion formation by targeting RhoA for degradation, Science, 2003, 302: 1775-9
[116] Ozdamar B, Bose R, Barrios-Rodiles M, et al. Regulation of the Polarity ProteinPar6 by TGFb Receptors Controls Epithelial Cell Plasticity, Science, 2005, 307: 1603-9
[117] Sahai E, Garcia-Medina R, Pouysségur J, et al. Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility, J Cell Biol, 2007, 176 (1): 35-42
[118] Yamashita M, Ying SX, Zhang GM, et al. Ubiquitin ligase Smurf1controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation, Cell, 2005, 121: 101-13
[119] Narimatsu M, Bose R, Pye M, et al. Regulation of Planar Cell Polarity by Smurf Ubiquitin Ligases, Cell, 2009, 137: 295–307
[120] Zhao M, Qiao M, Harris SE, et al. Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo, J Biol Chem, 2004, 279 (13): 12854-59
[121] Asanuma K, Yanagida-Asanuma E, Faul C, et al. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signaling, Nature Cell Biol, 2006, 8: 485–91
[122] Barrios-Rodiles M, Brown KR, Ozdamar B, et al. High-throughput mapping of a dynamic signaling network in mammalian cells, Science, 2005, 307: 1621-5
[123] Olsten ME, Canton DA, Zhang C, et al. The Pleckstrin homology domain of CK2 interacting protein-1 is required for interactions and recruitment of protein kinase CK2 to the plasma membrane, J Biol Chem, 2004, 279: 42114-27
[124] Canton DA, Olsten ME, Kim K, et al. The pleckstrin homology domain-containing protein CKIP-1 is involved in regulation of cell morphology and the actin cytoskeleton and interaction with actin capping protein, Mol CellBiol, 2005, 25: 3519-34
[125] Canton DA, Olsten ME, Niederstrasser H, et al. The role of CKIP-1 in cell morphology depends on its interaction with actin-capping protein, J Biol Chem, 2006, 281: 36347-59
[126] Safi A, Vandromme M, Caussanel S, et al. Role for the pleckstrin homology domain-containing protein CKIP-1 in phosphatidylinositol 3-kinase-regulated muscle differentiation, Mol Cell Biol, 2004, 24: 1245-55
[127] Tokuda E, Fujita N, Oh-hara T, et al. Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein,down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo, Cancer Res, 2007, 67: 9666-76
[128] Yu Y, Zhang C, Zhou G, et al. Gene expression profiling in human fetal liver and identification of tissue- and developmental-stage-specific genes through compiled expression profiles and efficient cloning of full-length cDNAs. Genome Res, 2001, 11: 1392-403
[129] Zhang L, Xing G, Tie Y, et al. Role for the pleckstrin homology domain-containing protein CKIP-1 in AP-1 regulation and apoptosis, EMBO J, 2005, 24: 766-78
[130] Zhang L, Tie Y, Tian C, et al. CKIP-1 recruits nuclear ATM partially to the plasma membrane through interaction with ATM, Cell Signal, 2006, 18: 1386-95
[131] Zhang L, Tang Y, Tie Y, et al. The PH domain containing protein CKIP-1 binds to IFP35 and Nmi and is involved in cytokine signaling, Cell Signal, 2007, 19: 932-44
[132] Xi S, Tie Y, Lu K, et al. N-terminal PH domain and C-terminal auto-inhibitory region of CKIP-1 coordinate to determine its nucleus-plasma membrane shuttling, FEBS Lett, 2010, 584(6): 1223-30
[133] Hill CS. Nucleocytoplasmic shuttling of Smad proteins, Cell Res, 2009, 19(1): 36-46
[134] Sudol M, Hunter T. New wrinkles for an old domain, 2000, Cell, 103: 1001–4
[135]尹秀山博士论文, CKIP-1基因的敲除小鼠模型建立及其在骨骼、免疫系统中的生理功能研究,军事医学科学院,2009, 22-35
[136] Lu K, Yin X, Weng T, et al. Targeting WW domains linker of HECT-typeubiquitin ligase Smurf1 for activation by CKIP-1, Nature Cell Biol, 2008, 10: 994-1002
[137] Lin X, Liang M, Feng XH. Smurf2 Is a Ubiquitin E3 Ligase Mediating Proteasome-dependent Degradation of Smad2 in Transforming Growth Factor-b Signaling, J Biol Chem , 2000, 275 (47): 36818–22
[138] Zhang Y,Chang C, Gehling D J,et al. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase,Proc Natl Acad Sci USA,2001, 98(3): 974–9
[139] Yang X, Matsuda K, Bialek P, et al. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology: implication for Coffin-Lowry Syndrome, 2004, Cell, 117: 387-98
[140] Ingham R J, Colwill K, Howard C, et al. WW Domains Provide a Platform for the Assembly of Multiprotein Networks, 2005, Mol Cell Biol, 25(16): 7092–7106
[141] Kaneki H, Guo R, Chen D, et al. Tumor Necrosis Factor Promotes Runx2 Degradation through Up-regulation of Smurf1 and Smurf2 in Osteoblasts, J Biol Chem, 2006, 281(7): 4326–33
[142] Guo R, Yamashita M, Zhang Q, et al. Ubiquitin Ligase Smurf1 Mediates Tumor Necrosis Factor-induced Systemic Bone Loss by Promoting Proteasomal Degradation of Bone Morphogenetic Signaling Proteins, J Biol Chem, 2008, 283(34): 23084–92
[143] Bar-Sagi D, Hall A. Ras and Rho GTPases: a family reunion, Cell, 2000, 103: 227-38
[144] Bishop AL, Hall A. Rho GTPases and their effector proteins, Biochem J, 2000, 348 (2):241-55
[145] Van Aelst L, Symons M. Role of Rho family GTPases in epithelial morphogenesis, Genes Dev, 2002, 16(9): 1032-54
[146] Grünert S, Jechlinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis, Nat Rev Mol Cell Biol, 2003, 4(8): 657-65
[147] Oft M, Heider KH, Beug H. TGF-beta signaling is necessary for carcinoma cell invasiveness and metastasis, Curr Biol, 1998, 8(23): 1243-52
[148] Siegel PM, MassaguéJ. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer, Nat Rev Cancer, 2003, 3(11): 807-21
[149] Rizo J, Sudhof TC. C2 domains, structure and function of a universal Ca2+-binding domain, J Biol Chem, 1998, 273: 15879-82
[150] Guerrero-Valeroa M, Ferrer-Ortab C, Querol-Audíb J, et al. Structural and mechanistic insights into the association of PKC-C2 domain to PtdIns(4, 5)P2, Proc Natl Acad Sci USA, 2009, 106: 6603–7
[1] Ciechanover A, Iwai K. The ubiquitin system: from basic mechanisms to the patient bed, IUBMB Life, 2004, 56: 193–201
[2] Guardavaccaro D, Pagano M. Oncogenic aberrations of cullin-dependent ubiquitin ligases, Oncogene,2004,23 (11):2037-2049
[3] Peoski MD, Deshaies RJ. Function and regulation of culling-RING ubiquitin ligases, Nat Rev Mol Cell Biol,2005,6(1): 9-2O
[4] Zheng N.A closer look of the HECTic ubiquitin ligases, Structure, 2003, 11(1):5-6
[5] Ogunjimi AA, Briant DJ, Pece-Barbara N, et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain, Mol Cell, 2005, 19: 297–308.
[6] Verdecia MA, Joazeiro CA, Wells NJ, et al. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase, Mol Cell, 2003, 11: 249–259
[7] ROlfe M,Beer-Romero P,Glass S,et a1.Reconstitution of p53-ubiquitinylation reactions from purified components:the role of human ubiquitin—conjugating enzyme UBC4 and E6 associated protein (E6AP), Proc Natl Acad Sci USA, 1995,92(8):3264-3268
[8] Shearwin-Whyatt L, Dalton HE, Foot N, et a1. Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins, Bioessays, 2006, 28: 617–628.
[9] Rotin D, Staub O, Haguenauer-Tsapis R. Ubiquitination and endocytosis of plasma membrane proteins: role of Nedd4/Rsp5p family of ubiquitin-protein ligases, J Membr Biol, 2000, 176(1): 1-17
[10] Tamai KK, Shimoda C. The novel HECT-type ubiquitin-protein ligase Pub2p shares partially overlapping function with Pub1p in Schizosaccharomyces pombe, J Cell Sci, 2002, 115(9): 1847-1857
[11] Huang K, Johnson KD, Petcherski AG, et al. A HECT domain ubiquitin ligase closely related to the mammalian protein WWP1 is essential for Caenorhabditis elegans embryogenesis, Gene, 2000, 252(1-2): 137-45
[12] Myat A, Henry P, McCabe V, et al. Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor, Neuron, 2002, 35(3): 447-59
[13] Podos SD, Hanson KK, Wang YC,et al. The DSmurf ubiquitin-protein ligase restricts BMP signaling spatially and temporally during Drosophila embryogenesis. Dev Cell, 2001, 1(4): 567-78
[14] Ingham RJ, Gish G, Pawson T. The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture, Oncogene, 2004, 23(11): 1972-84
[15] Kamynina E, Tauxe C, Staub O. Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation, Am J Physiol Renal Physiol, 2001, 281(3): 469-77
[16] Chen S, BhargavaA, Mastroberardino L, et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk, Proc Natl Acad Sci USA, 1999, 96: 2514-2519
[17] Snyder PM, Olson DR, Thomas BC. Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel, J Biol Chem, 2002, 277(1): 5-8
[18] Snyder PM, Olson DR, Kabra R, et al. cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2, J Biol Chem, 2004, 279(44): 45753-8
[19] Lee IH, Dinudom A, Sanchez-Perez A, et al. Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2, J Biol Chem, 2007, 282(41): 29866-73
[20] Edinger RS, Lebowitz J, Li H, et al. Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2, J Biol Chem, 2009, 284(1): 150-7
[21] Ichimura T, Yamamura H, Sasamoto K, et al. 14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation -dependent interaction with Nedd4-2 ubiquitin ligase, J Biol Chem, 2005, 280(13): 13187-94
[22] Bhalla V, Oyster NM, Fitch AC, et al. AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2, J Biol Chem, 2006, 281(36): 26159-69
[23] Gao M, Labuda T, Xia Y, et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch, Science, 2004, 306: 271–275.
[24] Gallagher E, Gao M, Liu YC, et al. Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change, Proc Natl Acad Sci USA, 2006, 103: 1717–1722.
[25] Yang C, Zhou W, Jeon MS, et al. Negative regulation of the E3 ubiquitin ligase itch viaFyn-mediated tyrosine phosphorylation, Mol Cell, 2006, 21(1): 135-41
[26] Chen C, Matesic LE. The Nedd4-like family of E3 ubiquitin ligases and cancer, Cancer Metastasis Rev, 2007, 26(3-4): 587-604
[27] Gallagher E, Gao M, Liu YC, et al. Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change, Proc Natl Acad Sci USA, 2006, 103(6): 1717-22
[28] Oberst A, Malatesta M, Aqeilan RI, et al. The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch, Proc Natl Acad Sci USA, 2007, 104: 11280
[29] Ogunjimi AA, Briant DJ, Pece-Barbara N, et al. Regulation of Smurf2 ubiquitin ligase activtity activity by anchoring the E2 to the HECT domain, Mol Cell, 2005, 19: 297–308
[30] Wiesner S, Ogunjimi AA, Wang HR,et al. Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain, Cell, 2007, 130(4): 651-62
[31] Bosc DG, Graham KC, Saulnier RB, et al. Identification and characterization of CKIP-1, a novel pleckstrin homology domain-containing protein that interacts with protein kinase CK2, J Biol Chem, 2000, 275(19): 14295-306
[32] Lu K, Yin X, Weng T,et al. Targeting WW domains linker of HECT-type ubiquitin ligase Smurf1 for activation by CKIP-1, Nature Cell Biol, 2008, 10(8): 994-1002
[33] Yamashita M, Ying SX, Zhang GM, et al. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation, Cell, 2005, 121(1): 101-13
[34] Izzi L, Attisano L. Ubiquitin-dependent regulation of TGFbeta signaling in cancer, Neoplasia, 2006, 8: 677–688
[35] Kavsak P, Rasmussen RK, Causing CG, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation, Mol Cell, 2000, 6(6): 1365-75
[36] Ebisawa T, Fukuchi M, Murakami G, et al. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation, J Biol Chem, 2001, 276(16): 12477-80
[37] Plant PJ, Lafont F, Lecat S, et al. Apical membrane targeting of Nedd4 is mediated by an association of Its C2 domain with Annexin XIIIb, J Cell Biol, 2000, 149: 1473–1484
[38] Kitching R, Wong MJ, Koehler D, et al. The RING-H2 protein RNF11 is differentially expressed in breast tumours and interacts with HECT-type E3 ligases, Biochim Biophys Acta, 2003, 1639(2): 104-12
[39] Li H, Seth A. An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein, Oncogene, 2004, 23(10): 1801-8
[40] Zhao M, Qiao M, Oyajobi BO, et al. E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation, J Biol Chem, 2003, 278(30): 27939-44
[41] Shen R, Chen M, Wang YJ, et al. Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation, J Biol Chem, 2006, 281(6): 3569-76
[42] Jones DC, Wein MN, Oukka M, et al. Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3, Science, 2006, 312(5777): 1223-7
[43] Hettema EH, Valdez-Taubas J, Pelham HR. Bsd2 binds the ubiquitin ligase Rsp5 andmediates the ubiquitination of transmembrane proteins, EMBO J, 2004, 23: 1279–1288
[44] Harvey KF, Shearwin-Whyatt LM, Fotia A, et al. N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein, J Biol Chem, 2002, 277: 9307–9317.
[45] Oliver PM, Cao X, Worthen GS, et al. Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation, Immunity, 2006, 25(6): 929-40
[46] Sangadala S, Boden SD, Viggeswarapu M, et al. LIM mineralization protein-1 potentiates bone morphogenetic protein responsiveness via a novel interaction with Smurf1 resulting in decreased ubiquitination of Smads, J Biol Chem, 2006, 281(25): 17212-9
[47] Wu X, Yen L, Irwin L, et al. Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8, Mol Cell Biol, 2004, 24: 7748–7757.
[48] Canning M, Boutell C, Parkinson J, et al. A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific protease USP7, J Biol Chem, 2004, 279: 38160–38168
[49] Kovalenko A, Chable-Bessia C, Cantarella G, et al. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination, Nature, 2003, 424: 801–805
[50] Kee Y, Lyon N, Huibregtse JM. The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme, EMBO J, 2005, 24(13): 2414-24
[51] Ren J, Kee Y, Huibregtse JM, et al. Hse1, a component of the yeast Hrs-STAM ubiquitin sorting complex, associates with ubiquitin peptidases and a ligase to control sorting efficiency into multivesicular bodies, Mol Biol Cell, 2007, 18(1): 324-35
[52] Mouchantaf R, Azakir BA, McPherson PS, et al. The ubiquitin ligase itch is uto-ubiquitylated in vivo and in vitro but is protected from degradation by interacting with the deubiquitylating enzyme FAM/USP9X, J Biol Chem, 2006, 281(50): 38738-47
[53] Ohashi N, Yamamoto T, Uchida C, et al. Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta, FEBS Letters, 2005, 579: 2557-2563.
[54] Kaneki H, Guo R, Chen D, et al. Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts, J Biol Chem, 2006, 281: 4326–4333
[55] Zhang H, Cohen SN. Smurf2 up-regulation activates telomere-dependent senescence, Genes Development, 2004, 18: 3028–3040
[56] Rossi M, Laurenzi D, Munarriz V, et al. The ubiquitin-protein ligase Itch regulates p73 stability, EMBO J, 2005, 24: 836–848.
[57] Laine A, Ronai Z. Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1, Oncogene, 2007, 26(10): 1477–1483
[2] Etlinger JD, Goldberg AL. A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes, Proc Natl Acad Sci USA, 1977, 74(1):54-8
[3] Hershko A, Tomkins GM. Studies on the degradation of tyrosine aminotransferase in hepatoma cells in culture. Influence of the composition of the medium and adenosine triphosphate dependence, J Biol Chem, 1971, 246(3):710-4
[4] Ciehanover A, Hod Y, Hershko A. A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes, Biochem Biophys Res Commun, 1978 , 81(4):1100-5
[5] Hershko A, Ciechanover A, Heller H, et al. Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis, Proc Natl Acad Sci USA, 1980, 77(4):1783-6
[6] Ciechanover A, Heller H, Elias S, et al. ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation, Proc Natl Acad Sci USA. 1980 ,77(3):1365-8
[7] Wilkinson KD, Urban MK, Haas AL. Ubiquitin is the ATP-dependent proteolysis factor I of rabbit reticulocytes, J Biol Chem, 1980, 255(16):7529-32
[8] Ciechanover A, Elias S, Heller H, et al. "Covalent affinity" purification of ubiquitin-activating enzyme, J Biol Chem, 1982, 257(5): 2537-42
[9] Hershko A, Heller H, Elias S, et al. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown, J Biol Chem, 1983, 258(13): 8206-14
[10] Hough R, Pratt G, Rechsteiner M. Ubiquitin-lysozyme conjugates: Identification and characterization of an ATP-dependent protease from rabbit reticulocyte lysates, J Biol Chem, 1986, 261(5): 2400-8
[11] Hough R, Pratt G, Rechsteiner M. Purification of two high molecular weight proteases from rabbit reticulocyte lysate, J Biol Chem, 1987, 262(17): 8303-13
[12] Hilt W, Wolf D H. Proteasomes: The World of Regulatory Proteolysis, LANDESBIOSCIENCE PUBLISHERS, 2001, 301
[13] Ciechanover A. The ubiquitin-proteasome pathway: on protein death and cell life, EMBO J, 1998, 17(24): 7151-60
[14] Ciechanover A, Iwai K. The ubiquitin system: from basic mechanisms to the patient bed, IUBMB Life, 2004, 56: 193-201
[15] Hoeller D, Hecker CM and Dikic I. Ubiquitin and ubiquitin-like proteins in cancer pathogenesis, Nat Rev Cancer, 2006, 6: 776-88
[16] Cook WJ, Bugg CE, Vijay-Kumar S. Structure of ubiquitin refined at 1.8 ? resolution, J Mol Biol, 1987, 194(3): 531-44
[17] Peoski MD, Deshaies RJ. Function and regulation of culling-RING ubiquitin ligases, Nat Rev Mol Cell Biol, 2005, 6(1): 9-20
[18] Zheng N.A closer look of the HECTic ubiquitin ligases, Structure, 2003, 11(1): 5-6
[19] Huang L, Kinnucan E, Wang G, et al. Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade, Science, 1999, 286(5443): 1321-6
[20] Verdecia MA, Joazeiro CA, Wells NJ. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase, Mol Cell, 2003, 11: 249–59
[21] Ogunjimi AA, Briant DJ, Pece-Barbara N, et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain, Mol Cell, 2005, 19: 297–308
[22] Kamadurai HB, Souphron J, Scott DC, et al. Insights into ubiquitin transfer cascades from a structure of a UbcH5B approximately ubiquitin-HECT (NEDD4L) complex, Mol Cell, 2009, 36: 1095-1102
[23] Pandya RK, Partridge JR, Love KR, et al. A structural element within the HUWE1 HECT domain modulates self-ubiquitination and substrate ubiquitination activities, J Biol Chem, 2010, 285(8): 5664-73
[24] ROlfe M,Beer-Romero P,Glass S,et a1.Reconstitution of p53-ubiquitinylation reactions from purified components:the role of human ubiquitin-conjugating enzyme UBC4 and E6 associated protein (E6AP), Proc Natl Acad Sci USA, 1995, 92(8): 3264-8
[25] Shearwin-Whyatt L, Dalton HE, Foot N, et a1. Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins, Bioessays,2006, 28: 617–28
[26] Ingham RJ, Gish G, Pawson T. The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture, Oncogene, 2004, 23(11): 1972-84
[27] Rotin D, Staub O, Haguenauer-Tsapis R. Ubiquitination and endocytosis of plasma membrane proteins: role of Nedd4/Rsp5p family of ubiquitin-protein ligases, J Membr Biol, 2000, 176(1): 1-17
[28] Tamai KK, Shimoda C. The novel HECT-type ubiquitin-protein ligase Pub2p shares partially overlapping function with Pub1p in Schizosaccharomyces pombe, J Cell Sci, 2002, 115(9): 1847-57
[29] Huang K, Johnson KD, Petcherski AG, et al. A HECT domain ubiquitin ligase closely related to the mammalian protein WWP1 is essential for Caenorhabditis elegans embryogenesis, Gene, 2000, 252(1-2): 137-45
[30] Myat A, Henry P, McCabe V, et al. Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor, Neuron, 2002, 35(3): 447-59
[31] Podos SD, Hanson KK, Wang YC, et al. The DSmurf ubiquitin-protein ligase restricts BMP signaling spatially and temporally during Drosophila embryogenesis, Dev Cell, 2001, 1(4): 567-78
[32] Chen C, Matesic LE. The Nedd4-like family of E3 ubiquitin ligases and cancer, Cancer Metastasis Rev, 2007, 26(3-4): 587-604
[33] Kamynina E, Tauxe C, Staub O. Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation, Am J Physiol Renal Physiol, 2001, 281(3): 469-77
[34] Myat A, Henry P, McCabe V, et al. Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor, Neuron, 2002, 35(3): 447-59
[35] Chen S, BhargavaA, Mastroberardino L, et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk, Proc Natl Acad Sci USA, 1999, 96: 2514-9
[36] Snyder PM, Olson DR, Thomas BC. Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel, J Biol Chem, 2002, 277(1): 5-8
[37] Ichimura T, Yamamura H, Sasamoto K, et al. 14-3-3 proteins modulate theexpression of epithelial Na+ channels by phosphorylation -dependent interaction with Nedd4-2 ubiquitin ligase, J Biol Chem, 2005, 280(13): 13187-94
[38] Bhalla V, DaidiéD, Li H, et al. Serum- and glucocorticoid-regulated kinase 1 regulates ubiquitin ligase neural precursor cell-expressed developmentally down-regulated protein 4-2 by inducing interaction with 14-3-3, Mol Endocrinol, 2005, 19(12): 3073-84
[39] Snyder PM, Olson DR, Kabra R, et al. cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2, J Biol Chem, 2004, 279(44): 45753-8
[40] Lee IH, Dinudom A, Sanchez-Perez A, et al. Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2, J Biol Chem, 2007, 282(41): 29866-73
[41] Edinger RS, Lebowitz J, Li H, et al. Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2, J Biol Chem, 2009, 284(1): 150-7
[42] Bhalla V, Oyster NM, Fitch AC, et al. AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2, J Biol Chem, 2006, 281(36): 26159-69
[43] Bhalla V, Daidie D, Li H , et al. Serum and glucocorticoid regulated kinase 1 regulates ubiquitin ligase neural precursor cell expressed, developmentally down regulated protein 4-2 by interaction with 14-3-3, Mol Endocrinol, 2005, 19: 3073-84
[44] Gao M, Labuda T, Xia Y, et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch, Science, 2004, 306: 271–5
[45] Tanoue T, Maeda R, Adachi M, et al. Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions, EMBO J, 2001, 20: 466–79
[46] Gallagher E, Gao M, Liu YC, et al. Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change, Proc Natl Acad Sci USA, 2006, 103: 1717–22.
[47] Yang C, Zhou W, Jeon MS, et al. Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation, Mol Cell, 2006, 21(1): 135-41
[48] Nuber U, Schwarz SE, Scheffner M. The ubiquitin-protein ligase E6-associated protein (E6-AP) serves as its own Substrate, Eur J Biochem, 1998, 254, 643-9
[49] Oberst A, Malatesta M, Aqeilan RI, et al. The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch, Proc Natl Acad Sci USA, 2007, 104: 11280-5
[50] Wiesner S, Ogunjimi AA, Wang HR, et al. Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain, Cell, 2007, 130(4): 651-62
[51] Kavsak P, Rasmussen RK, Causing CG, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation, Mol Cell, 2000, 6(6): 1365-75
[52] Ebisawa T, Fukuchi M, Murakami G, et al. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation, J Biol Chem, 2001, 276(16): 12477-80
[53] Plant PJ, Lafont F, Lecat S, et al. Apical membrane targeting of Nedd4 is mediated by an association of Its C2 domain with Annexin XIIIb, J Cell Biol, 2000, 149: 1473-84
[54] Kitching R, Wong MJ, Koehler D, et al. The RING-H2 protein RNF11 is differentially expressed in breast tumors and interacts with HECT-type E3 ligases, Biochim Biophys Acta, 2003, 1639(2): 104-12
[55] Li H, Seth A. An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein, Oncogene, 2004, 23(10): 1801-8
[56] Zhao M, Qiao M, Oyajobi B, et al. E3 ubiquitin ligase Smurf1 mediates core-binding factorα1/Runx2 degradation and plays a specific role in osteoblast differentiation, J Biol Chem, 2003, 278 (30): 27939-44
[57] Shen R, Chen M, Wang YJ, et al. Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation, J Biol Chem, 2006, 281(6): 3569-76
[58] Jones DC, Wein MN, Oukka M, et al. Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3, Science, 2006, 312: 1223-7
[59] Hettema EH, Valdez-Taubas J, Pelham HR. Bsd2 binds the ubiquitin ligase Rsp5 and mediates the ubiquitination of transmembrane proteins, EMBO J, 2004, 23: 1279-88
[60] Harvey KF, Shearwin-Whyatt LM, Fotia A, et al. N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associatedprotein, J Biol Chem, 2002, 277: 9307–17
[61] Oliver PM, Cao X, Worthen GS, et al. Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation, Immunity, 2006, 25(6): 929-40
[62] Sangadala S, Boden SD, Viggeswarapu M, et al. LIM mineralization protein-1 potentiates bone morphogenetic protein responsiveness via a novel interaction with Smurf1 resulting in decreased ubiquitination of Smads, J Biol Chem, 2006, 281(25): 17212-9
[63] Kee Y, Lyon N, Huibregtse JM. The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme, EMBO J, 2005, 24(13): 2414-24
[64] Mouchantaf R, Azakir BA, McPherson PS, et al. The ubiquitin ligase itch is auto-ubiquitylated in vivo and in vitro but is protected from degradation by interacting with the deubiquitylating enzyme FAM/USP9X, J Biol Chem, 2006, 281(50): 38738-47
[65] Flasza M, Gorman P, Roylance R. Alternative splicing determines the domain structure of WWP1, a Nedd4 family protein, Biochem Biophy Res Commun, 2002, 290: 431–7
[66] Qi H, Grenier J, Fournier A, et al. Androgens differentially regulate the expression of NEDD4L transcripts in LNCaP human prostate cancer cells, Mol Cell Endocrin, 2003, 210: 51–62
[67] Ohashi N, Yamamoto T, Uchida C, et al. Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta, FEBS Lett, 2005, 579: 2557-63
[68] Kaneki H, Guo R, Chen D, et al. Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts, J Biol Chem, 2006, 281: 4326–33
[69] Judge AR, Koncarevic A, Hunter RB, et al. Role for IkappaBalpha, but not c-Rel, in skeletal muscle atrophy, Am J Physiol, 2007, 292: C372–82
[70] Zhang H, Cohen SN. Smurf2 up-regulation activates telomere-dependent senescence, Genes Dev, 2004, 18: 3028–40
[71] Gu Z, Rubin MA, Yang Y, et al. Reg IV: A promising marker of hormone refractory metastatic prostate cancer, Clin Cancer Res, 2005, 11: 2237–43
[72] Imhof MO, McDonnell D P. Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by humanprogesterone and glucocorticoid receptors, Mol Cell Biol, 1996,16: 2594–2605
[73] Rossi M, De Laurenzi V, Munarriz E, et al. The ubiquitin-protein ligase Itch regulates p73 stability, EMBO J, 2005, 24: 836–48
[74] Laine A , Ronai Z. Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1, Oncogene, 2007, 26:1477–83
[75] Yang Y, Kitagaki J, Wang H, et al. Targeting the ubiquitin-proteasome system for cancer therapy, Cancer Sci, 2009, 100 (1): 24–8
[76] Eldridge AG , O’Brien T. Therapeutic strategies within the ubiquitin proteasome system, Cell Death Differ, 2010, 17: 4–13
[77] Bernassola F, Karin M, Ciechanover A, et al. The HECT family of E3 ubiquitin ligases: multiple players in cancer development, Cancer Cell, 2008, 14: 10-21
[78] Rotin D, Kumar S. Physiological functions of the HECT family of ubiquitin ligases, Nat Rev Mol Cell Biol, 2009, 10: 398-409
[79] Martin S, Olivier S. HECT E3s and human disease, BMC Biochemistry, 2007, 8 (Suppl 1): S6
[80] Kee Y, Huibregtse JM. Regulation of catalytic activities of HECT ubiquitin ligase, Biochem Biophyl Res Commun, 2007, 354: 329–33
[81] Lee NK, Lee SY. Modulation of Life and Death by the Tumor Necrosis Factor Receptor- Associated Factors (TRAFs), J Biochem Mol Biol, 2002, 35(1): 61-6
[82] Bishop GA, Moore CR, Xie P et al. TRAF proteins in CD40 signaling, Adv Exp Med Biol, 2007, 597:131–51
[83] Chung J, Park YC, Ye H et al. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci, 2002, 115: 679–88
[84] Rothe M,Wong SC,Henzel WJ, et al. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor, Cel1, 1994, 78: 68l-92
[85] Cao ZD,Xiong J,Takeuchi M, et a1.TRAF6 is a signal transducer for Interleukin-1, Nature, 1996, 383: 443-6
[86] Malinin NL,Boldin MP,Kovalenko AV, et a1.MAP3K-related kinase involved in NF-κB induction by TNF-α,CD95 and IL-1, Nature, 1997, 385: 540-4
[87] Cheng G, Baltimore D.TANK, a co-inducer with TRAF2 of TNF and CD40L-mediated NF-κB activation, Genes Dev, 1996,10: 963-73
[88] Song HY , Regnier CH , Kirschning CJ, et a1 . Tumor necrosisfactor(TNF)-mediated kinase cascades:Bifurcation of nuclear factor-κB and c-jun N-terminal kinase(JNK/SAPK)pathways at TNF receptor associated factor 2, Proc Natl Acad Sci USA, 1997, 94: 9792-6
[89] Rothe M,Pan MG,Henzel WJ, et a1.The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins, Cell, 1995, 83: 1243-52
[90] Park YC,Burkitt V,Villa AR,et a1.Structural basis for self-association and receptor recognition of human TRAF2, Nature, 1999, 398: 533-8
[91] Freemont PS.RING for destruction? Curr Bio1, 2000,10:R84-87
[92] Dadgostar H,Cheng G.An intact zinc ring finger is required for tumor necrosis factor receptor associated factor mediated nuclear factor-κB activation but is dispensable for c-Jun N-terminal kinase signaling, J Biol Chem, 1998, 273: 24775-80
[93] Pineda G,Ea CK,Chen ZJ.Ubiquitination and TRAF signaling.Adv Exp Med Bio1, 2007, 597: 80-92
[94] Chen ZJ. Ubiquitin signalling in the NF-κB pathway, Nat Cell Boil, 2005, 7:758-766
[95] Wang C. Deng L, Hong M, et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK, Nature, 2001, 412: 346–51
[96] Kanayama A, Seth RB, Sun L, et al. TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains, Mol Cell, 2004 15: 535–48
[97] Shi CS and Kehrl JH. Tumor necrosis factor (TNF)-induced germinal center kinase related (GCKR) and stress-activated protein kinase (SAPK) activation depends upon the E2/E3 complex Ubc13-Uev1A/TNF receptor-associated factor 2 (TRAF2), J Biol Chem, 2003, 278: 15429–34
[98] Habelhah H, Takahashi S, Cho SG, et al. Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF-κB, EMBO J, 2004, 23: 322–32
[99] Lee TH, Shank J, Cusson N, et al. The kinase activity of Rip1 is not required for tumor necrosis factor-alpha-induced IκB kinase or p38 MAP kinase activation or for the ubiquitination of Rip1 by Traf2, J Biol Chem, 2004, 279: 33185–191
[100] Hofmann RM, Pickart CM. Noncanonical MMS2-encoded ubiquitin conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair, Cell, 1999, 96: 645–53
[101] Jang H D, Chung YM, Baik JY, et al. Caspase-cleaved TRAF1 negatively regulates the antiapoptotic signals of TRAF2 during TNF-induced cell death, Biochem Biophy Res Commun, 2001, 281: 499-505
[102] Zheng C, Kabaleeswaran V, Wang Y, et al. Crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes: affinity, specificity, and regulation , Mol Cell, 2010, 38: 101-13
[103] Tsitsikov EN, Laouin D, Dunn I F, et al. TRAF1 is a negative regulator of TNF signaling: enhanced TNF signaling in TRAF1-deficient mice, Immunity, 2001, 15: 647-57
[104] Yeh W C, Shahinian A, Speiser D, et al. Early lethality, functional NF-κB activation and increased sensitivity to TNF-induced cell death in TRAF2 deficient mice, Immunity, 1997, 7: 715-25
[105] Hauer J, Püschner S, Ramakrishnan P, et al. TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs, Proc Natl Acad Sci USA, 2005, 102: 2874-9
[106] Kedinger V, Alpy F, Tomasetto C, et al. Spatial and temporal distribution of the traf4 genes during zebrafish development, Gene Expr Patterns, 2005, 5(4): 545-52
[107] Tada K, Okazaki T, Sakon S, et al. Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death, J Biol Chem, 2001, 276(39): 36530-4
[108] Chung JY, Lu M, Yin Q, et al. Molecular basis for the unique specificity of TRAF6, Adv Exp Med Biol, 2007, 597: 122-30
[109] Lee NK, Choi YG, Baik JY, et al. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation, Blood, 2005, 106(3): 852-9
[110] Ohazama A, Courtney JM, Tucker AS, et al. Traf6 is essential for murine tooth cusp morphogenesis, Dev Dyn, 2004, 229(1):131-5
[111] Zhu H, Kavsak P, Abdollah S, et al. SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation, Nature, 1999, 400: 687-93
[112] Tajima Y, GotoK, Yoshida M, et al. Chromosomal Region Maintenance 1 (CRM1)-dependent Nuclear Export of Smad Ubiquitin Regulatory Factor 1 (Smurf1) Is Essential for Negative Regulation of Transforming Growth Factor-Signaling by Smad7, J Biol Chem, 2003, 278(12): 10716–21
[113] Suzuki C, Murakami G, Fukuchi M,et al. Smurf1 Regulates the Inhibitory Activity of Smad7 by Targeting Smad7 to the Plasma Membrane,J Biol Chem, 2002,277(42): 39919–25
[114] Bellido T, Ali AA, Plotkin LI, et al. Proteasomal Degradation of Runx2 Shortens Parathyroid Hormone-induced Anti-apoptotic Signaling in Osteoblasts, 2003, J Biol Chem, 278(50): 50259–72
[115] Wang HR, Zhang Y, Ozdamar B, et al. Regulation of cell polarity and protrusion formation by targeting RhoA for degradation, Science, 2003, 302: 1775-9
[116] Ozdamar B, Bose R, Barrios-Rodiles M, et al. Regulation of the Polarity ProteinPar6 by TGFb Receptors Controls Epithelial Cell Plasticity, Science, 2005, 307: 1603-9
[117] Sahai E, Garcia-Medina R, Pouysségur J, et al. Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility, J Cell Biol, 2007, 176 (1): 35-42
[118] Yamashita M, Ying SX, Zhang GM, et al. Ubiquitin ligase Smurf1controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation, Cell, 2005, 121: 101-13
[119] Narimatsu M, Bose R, Pye M, et al. Regulation of Planar Cell Polarity by Smurf Ubiquitin Ligases, Cell, 2009, 137: 295–307
[120] Zhao M, Qiao M, Harris SE, et al. Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo, J Biol Chem, 2004, 279 (13): 12854-59
[121] Asanuma K, Yanagida-Asanuma E, Faul C, et al. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signaling, Nature Cell Biol, 2006, 8: 485–91
[122] Barrios-Rodiles M, Brown KR, Ozdamar B, et al. High-throughput mapping of a dynamic signaling network in mammalian cells, Science, 2005, 307: 1621-5
[123] Olsten ME, Canton DA, Zhang C, et al. The Pleckstrin homology domain of CK2 interacting protein-1 is required for interactions and recruitment of protein kinase CK2 to the plasma membrane, J Biol Chem, 2004, 279: 42114-27
[124] Canton DA, Olsten ME, Kim K, et al. The pleckstrin homology domain-containing protein CKIP-1 is involved in regulation of cell morphology and the actin cytoskeleton and interaction with actin capping protein, Mol CellBiol, 2005, 25: 3519-34
[125] Canton DA, Olsten ME, Niederstrasser H, et al. The role of CKIP-1 in cell morphology depends on its interaction with actin-capping protein, J Biol Chem, 2006, 281: 36347-59
[126] Safi A, Vandromme M, Caussanel S, et al. Role for the pleckstrin homology domain-containing protein CKIP-1 in phosphatidylinositol 3-kinase-regulated muscle differentiation, Mol Cell Biol, 2004, 24: 1245-55
[127] Tokuda E, Fujita N, Oh-hara T, et al. Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein,down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo, Cancer Res, 2007, 67: 9666-76
[128] Yu Y, Zhang C, Zhou G, et al. Gene expression profiling in human fetal liver and identification of tissue- and developmental-stage-specific genes through compiled expression profiles and efficient cloning of full-length cDNAs. Genome Res, 2001, 11: 1392-403
[129] Zhang L, Xing G, Tie Y, et al. Role for the pleckstrin homology domain-containing protein CKIP-1 in AP-1 regulation and apoptosis, EMBO J, 2005, 24: 766-78
[130] Zhang L, Tie Y, Tian C, et al. CKIP-1 recruits nuclear ATM partially to the plasma membrane through interaction with ATM, Cell Signal, 2006, 18: 1386-95
[131] Zhang L, Tang Y, Tie Y, et al. The PH domain containing protein CKIP-1 binds to IFP35 and Nmi and is involved in cytokine signaling, Cell Signal, 2007, 19: 932-44
[132] Xi S, Tie Y, Lu K, et al. N-terminal PH domain and C-terminal auto-inhibitory region of CKIP-1 coordinate to determine its nucleus-plasma membrane shuttling, FEBS Lett, 2010, 584(6): 1223-30
[133] Hill CS. Nucleocytoplasmic shuttling of Smad proteins, Cell Res, 2009, 19(1): 36-46
[134] Sudol M, Hunter T. New wrinkles for an old domain, 2000, Cell, 103: 1001–4
[135]尹秀山博士论文, CKIP-1基因的敲除小鼠模型建立及其在骨骼、免疫系统中的生理功能研究,军事医学科学院,2009, 22-35
[136] Lu K, Yin X, Weng T, et al. Targeting WW domains linker of HECT-typeubiquitin ligase Smurf1 for activation by CKIP-1, Nature Cell Biol, 2008, 10: 994-1002
[137] Lin X, Liang M, Feng XH. Smurf2 Is a Ubiquitin E3 Ligase Mediating Proteasome-dependent Degradation of Smad2 in Transforming Growth Factor-b Signaling, J Biol Chem , 2000, 275 (47): 36818–22
[138] Zhang Y,Chang C, Gehling D J,et al. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase,Proc Natl Acad Sci USA,2001, 98(3): 974–9
[139] Yang X, Matsuda K, Bialek P, et al. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology: implication for Coffin-Lowry Syndrome, 2004, Cell, 117: 387-98
[140] Ingham R J, Colwill K, Howard C, et al. WW Domains Provide a Platform for the Assembly of Multiprotein Networks, 2005, Mol Cell Biol, 25(16): 7092–7106
[141] Kaneki H, Guo R, Chen D, et al. Tumor Necrosis Factor Promotes Runx2 Degradation through Up-regulation of Smurf1 and Smurf2 in Osteoblasts, J Biol Chem, 2006, 281(7): 4326–33
[142] Guo R, Yamashita M, Zhang Q, et al. Ubiquitin Ligase Smurf1 Mediates Tumor Necrosis Factor-induced Systemic Bone Loss by Promoting Proteasomal Degradation of Bone Morphogenetic Signaling Proteins, J Biol Chem, 2008, 283(34): 23084–92
[143] Bar-Sagi D, Hall A. Ras and Rho GTPases: a family reunion, Cell, 2000, 103: 227-38
[144] Bishop AL, Hall A. Rho GTPases and their effector proteins, Biochem J, 2000, 348 (2):241-55
[145] Van Aelst L, Symons M. Role of Rho family GTPases in epithelial morphogenesis, Genes Dev, 2002, 16(9): 1032-54
[146] Grünert S, Jechlinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis, Nat Rev Mol Cell Biol, 2003, 4(8): 657-65
[147] Oft M, Heider KH, Beug H. TGF-beta signaling is necessary for carcinoma cell invasiveness and metastasis, Curr Biol, 1998, 8(23): 1243-52
[148] Siegel PM, MassaguéJ. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer, Nat Rev Cancer, 2003, 3(11): 807-21
[149] Rizo J, Sudhof TC. C2 domains, structure and function of a universal Ca2+-binding domain, J Biol Chem, 1998, 273: 15879-82
[150] Guerrero-Valeroa M, Ferrer-Ortab C, Querol-Audíb J, et al. Structural and mechanistic insights into the association of PKC-C2 domain to PtdIns(4, 5)P2, Proc Natl Acad Sci USA, 2009, 106: 6603–7
[1] Ciechanover A, Iwai K. The ubiquitin system: from basic mechanisms to the patient bed, IUBMB Life, 2004, 56: 193–201
[2] Guardavaccaro D, Pagano M. Oncogenic aberrations of cullin-dependent ubiquitin ligases, Oncogene,2004,23 (11):2037-2049
[3] Peoski MD, Deshaies RJ. Function and regulation of culling-RING ubiquitin ligases, Nat Rev Mol Cell Biol,2005,6(1): 9-2O
[4] Zheng N.A closer look of the HECTic ubiquitin ligases, Structure, 2003, 11(1):5-6
[5] Ogunjimi AA, Briant DJ, Pece-Barbara N, et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain, Mol Cell, 2005, 19: 297–308.
[6] Verdecia MA, Joazeiro CA, Wells NJ, et al. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase, Mol Cell, 2003, 11: 249–259
[7] ROlfe M,Beer-Romero P,Glass S,et a1.Reconstitution of p53-ubiquitinylation reactions from purified components:the role of human ubiquitin—conjugating enzyme UBC4 and E6 associated protein (E6AP), Proc Natl Acad Sci USA, 1995,92(8):3264-3268
[8] Shearwin-Whyatt L, Dalton HE, Foot N, et a1. Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins, Bioessays, 2006, 28: 617–628.
[9] Rotin D, Staub O, Haguenauer-Tsapis R. Ubiquitination and endocytosis of plasma membrane proteins: role of Nedd4/Rsp5p family of ubiquitin-protein ligases, J Membr Biol, 2000, 176(1): 1-17
[10] Tamai KK, Shimoda C. The novel HECT-type ubiquitin-protein ligase Pub2p shares partially overlapping function with Pub1p in Schizosaccharomyces pombe, J Cell Sci, 2002, 115(9): 1847-1857
[11] Huang K, Johnson KD, Petcherski AG, et al. A HECT domain ubiquitin ligase closely related to the mammalian protein WWP1 is essential for Caenorhabditis elegans embryogenesis, Gene, 2000, 252(1-2): 137-45
[12] Myat A, Henry P, McCabe V, et al. Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor, Neuron, 2002, 35(3): 447-59
[13] Podos SD, Hanson KK, Wang YC,et al. The DSmurf ubiquitin-protein ligase restricts BMP signaling spatially and temporally during Drosophila embryogenesis. Dev Cell, 2001, 1(4): 567-78
[14] Ingham RJ, Gish G, Pawson T. The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture, Oncogene, 2004, 23(11): 1972-84
[15] Kamynina E, Tauxe C, Staub O. Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation, Am J Physiol Renal Physiol, 2001, 281(3): 469-77
[16] Chen S, BhargavaA, Mastroberardino L, et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk, Proc Natl Acad Sci USA, 1999, 96: 2514-2519
[17] Snyder PM, Olson DR, Thomas BC. Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel, J Biol Chem, 2002, 277(1): 5-8
[18] Snyder PM, Olson DR, Kabra R, et al. cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2, J Biol Chem, 2004, 279(44): 45753-8
[19] Lee IH, Dinudom A, Sanchez-Perez A, et al. Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2, J Biol Chem, 2007, 282(41): 29866-73
[20] Edinger RS, Lebowitz J, Li H, et al. Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2, J Biol Chem, 2009, 284(1): 150-7
[21] Ichimura T, Yamamura H, Sasamoto K, et al. 14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation -dependent interaction with Nedd4-2 ubiquitin ligase, J Biol Chem, 2005, 280(13): 13187-94
[22] Bhalla V, Oyster NM, Fitch AC, et al. AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2, J Biol Chem, 2006, 281(36): 26159-69
[23] Gao M, Labuda T, Xia Y, et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch, Science, 2004, 306: 271–275.
[24] Gallagher E, Gao M, Liu YC, et al. Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change, Proc Natl Acad Sci USA, 2006, 103: 1717–1722.
[25] Yang C, Zhou W, Jeon MS, et al. Negative regulation of the E3 ubiquitin ligase itch viaFyn-mediated tyrosine phosphorylation, Mol Cell, 2006, 21(1): 135-41
[26] Chen C, Matesic LE. The Nedd4-like family of E3 ubiquitin ligases and cancer, Cancer Metastasis Rev, 2007, 26(3-4): 587-604
[27] Gallagher E, Gao M, Liu YC, et al. Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change, Proc Natl Acad Sci USA, 2006, 103(6): 1717-22
[28] Oberst A, Malatesta M, Aqeilan RI, et al. The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch, Proc Natl Acad Sci USA, 2007, 104: 11280
[29] Ogunjimi AA, Briant DJ, Pece-Barbara N, et al. Regulation of Smurf2 ubiquitin ligase activtity activity by anchoring the E2 to the HECT domain, Mol Cell, 2005, 19: 297–308
[30] Wiesner S, Ogunjimi AA, Wang HR,et al. Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain, Cell, 2007, 130(4): 651-62
[31] Bosc DG, Graham KC, Saulnier RB, et al. Identification and characterization of CKIP-1, a novel pleckstrin homology domain-containing protein that interacts with protein kinase CK2, J Biol Chem, 2000, 275(19): 14295-306
[32] Lu K, Yin X, Weng T,et al. Targeting WW domains linker of HECT-type ubiquitin ligase Smurf1 for activation by CKIP-1, Nature Cell Biol, 2008, 10(8): 994-1002
[33] Yamashita M, Ying SX, Zhang GM, et al. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation, Cell, 2005, 121(1): 101-13
[34] Izzi L, Attisano L. Ubiquitin-dependent regulation of TGFbeta signaling in cancer, Neoplasia, 2006, 8: 677–688
[35] Kavsak P, Rasmussen RK, Causing CG, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation, Mol Cell, 2000, 6(6): 1365-75
[36] Ebisawa T, Fukuchi M, Murakami G, et al. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation, J Biol Chem, 2001, 276(16): 12477-80
[37] Plant PJ, Lafont F, Lecat S, et al. Apical membrane targeting of Nedd4 is mediated by an association of Its C2 domain with Annexin XIIIb, J Cell Biol, 2000, 149: 1473–1484
[38] Kitching R, Wong MJ, Koehler D, et al. The RING-H2 protein RNF11 is differentially expressed in breast tumours and interacts with HECT-type E3 ligases, Biochim Biophys Acta, 2003, 1639(2): 104-12
[39] Li H, Seth A. An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein, Oncogene, 2004, 23(10): 1801-8
[40] Zhao M, Qiao M, Oyajobi BO, et al. E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation, J Biol Chem, 2003, 278(30): 27939-44
[41] Shen R, Chen M, Wang YJ, et al. Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation, J Biol Chem, 2006, 281(6): 3569-76
[42] Jones DC, Wein MN, Oukka M, et al. Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3, Science, 2006, 312(5777): 1223-7
[43] Hettema EH, Valdez-Taubas J, Pelham HR. Bsd2 binds the ubiquitin ligase Rsp5 andmediates the ubiquitination of transmembrane proteins, EMBO J, 2004, 23: 1279–1288
[44] Harvey KF, Shearwin-Whyatt LM, Fotia A, et al. N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein, J Biol Chem, 2002, 277: 9307–9317.
[45] Oliver PM, Cao X, Worthen GS, et al. Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation, Immunity, 2006, 25(6): 929-40
[46] Sangadala S, Boden SD, Viggeswarapu M, et al. LIM mineralization protein-1 potentiates bone morphogenetic protein responsiveness via a novel interaction with Smurf1 resulting in decreased ubiquitination of Smads, J Biol Chem, 2006, 281(25): 17212-9
[47] Wu X, Yen L, Irwin L, et al. Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8, Mol Cell Biol, 2004, 24: 7748–7757.
[48] Canning M, Boutell C, Parkinson J, et al. A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific protease USP7, J Biol Chem, 2004, 279: 38160–38168
[49] Kovalenko A, Chable-Bessia C, Cantarella G, et al. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination, Nature, 2003, 424: 801–805
[50] Kee Y, Lyon N, Huibregtse JM. The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme, EMBO J, 2005, 24(13): 2414-24
[51] Ren J, Kee Y, Huibregtse JM, et al. Hse1, a component of the yeast Hrs-STAM ubiquitin sorting complex, associates with ubiquitin peptidases and a ligase to control sorting efficiency into multivesicular bodies, Mol Biol Cell, 2007, 18(1): 324-35
[52] Mouchantaf R, Azakir BA, McPherson PS, et al. The ubiquitin ligase itch is uto-ubiquitylated in vivo and in vitro but is protected from degradation by interacting with the deubiquitylating enzyme FAM/USP9X, J Biol Chem, 2006, 281(50): 38738-47
[53] Ohashi N, Yamamoto T, Uchida C, et al. Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta, FEBS Letters, 2005, 579: 2557-2563.
[54] Kaneki H, Guo R, Chen D, et al. Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts, J Biol Chem, 2006, 281: 4326–4333
[55] Zhang H, Cohen SN. Smurf2 up-regulation activates telomere-dependent senescence, Genes Development, 2004, 18: 3028–3040
[56] Rossi M, Laurenzi D, Munarriz V, et al. The ubiquitin-protein ligase Itch regulates p73 stability, EMBO J, 2005, 24: 836–848.
[57] Laine A, Ronai Z. Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1, Oncogene, 2007, 26(10): 1477–1483