PTPA对PP2A_c Y307磷酸化水平的作用及其机制
摘要
阿尔茨海默病(Alzheimer’s disease, AD)是一种渐进性的记忆丢失和认知功能损伤的神经退行性疾病,AD患者脑内两大特征性病理学改变是神经元内形成大量神经原纤维缠结(neurofibrillary tangles, NFT),以及细胞间大量老年斑(senile plaques, SP)的沉积。其中,神经原纤维缠结的主要成分是异常磷酸化的tau蛋白。人体内有107个酪氨酸磷酸酯酶,其中PP2A属于PPP家族,在AD发生发展过程中发挥重要的磷酸酯酶作用,影响着tau的磷酸化。PP2A催化亚基的活性调节方式主要有:改变PP2AC的表达水平以及对PP2AC翻译后修饰——Leu309甲基化和Tyr307磷酸化。PTPA是一种普遍存在于哺乳动物组织和细胞的蛋白,PTPA能够通过改变PP2AC空间构象和增加Leu309位点甲基化水平来增强PP2A磷酸酯酶的活性,但对PP2AC的Tyr307位点磷酸化水平是否存在作用,目前尚不清楚。
目的:研究PTPA对PP2AC Tyr307位点磷酸化水平的影响及其可能机制。
材料和方法:构建PTPA野生型质粒(wt-PTPA)和特异性针对PTPA基因序列的RNA干扰质粒pSUPER-siPTPA(siPTPA),分别转染入HEK293/tau细胞系,蛋白免疫印迹技术检测tau蛋白各位点磷酸化水平,检测与tau磷酸化相关的激酶、PP2AC蛋白、PP2AC去甲基化、磷酸化水平的变化。用PP2A活性试剂盒检测转染PP2A活性变化;用细胞免疫荧光观察PTPA与tau的磷酸化位点的细胞共定位;用RT-PCR方法检测PTP1B转录水平变化。
结果:(1) wtPTPA有效地增加了PTPA的表达,pSUP-siPTPA有效地降低了PTPA的表达;(2)293/tau细胞内过表达PTPA可以降低tau磷酸化水平,敲除PTPA使tau蛋白磷酸化水平增加;(3)调控PTPA表达水平可改变PP2A活性,但对GSK-3β没有影响;(4)OA可逆转过表达PTPA后对tau磷酸化水平的降低;(5)过表达PTPA能降低PP2AC Y307磷酸化水平;PTPA敲除后PP2ACY307磷酸化水平升高;(6)过表达PTPA能增加PP2AC Y307位点磷酸酯酶PTP1B的转录和蛋白表达水平;PTPA敲除后PTP1B的转录和蛋白表达水平降低,而其他引起PP2AC Y307变化的激酶没有发生变化。
结论:PTPA调控PTP1B的mRNA和蛋白水平而影响PP2AC307位点酪氨酸磷酸化。
Alzheimer's disease (Alzheimer's disease, AD) is a progressive memory loss and cognitive impairment in neurodegenerative disease, the characteristic pathological changes in the brain is: neurofibrillary tangles (NFT) in neurons and senile plaques (senile plaques, SP). The main component of neurofibrillary tangles is the abnormal phosphorylated tau protein. 107 types of tyrosine phosphatases are in human body; PP2A belongs to PPP family, and plays an important role in tau phosphorylation. PP2A catalytic subunit is regulated by catalytic subunit level and posttranslational modification, for example methylation at Leu309 and phosphorylation at Tyr307. PTPA, exists in animal tissues and cells, could activate PP2A via changing PP2AC space conformation and increasing methylation level at Leu309 by PME. It’s not clear whether PTPA has effects on Tyr307 phosphorylationai level.
Objective: To explore the effects of PTPA on PP2AC Y307 phosphorylational level and the underlying mechanism.
Materials and Methods: PTPA wild type plasmid (wt-PTPA) and siPTPA (pSUPER-siPTPA) were constructed and transfected into HEK293/tau cells. Proteins levels were detected by Western blotting and Immunofluorescence, PP2A actvity was detected by protein phosphatase activity assay kit, RT-PCR was used to deteced PTP1B mRNA.
Results: (1) Overexpression of PTPA reduces tau phosphorylation level, knockdown of PTPA increases tau phosphorylation level; (2) Overexpression of PTPA increases PP2A activity, PTPA knockdown decreases PP2A activity; (3) PTPA regulates PP2AC Y307 phosphorylation and PP2Ac L309 methylation level, but has no obvious effects on other major enzymes which regulate tau phosphorylation; (4) Overexpression of PTPA increases PTP1B mRNA and protein levels; PTPA knockdown decreases PTP1B mRNA and protein levels.
Conclusion: PTPA can regulate PP2AC Y307 phosphorylation level by changing PTP1B mRNA and protein level.
目的:研究PTPA对PP2AC Tyr307位点磷酸化水平的影响及其可能机制。
材料和方法:构建PTPA野生型质粒(wt-PTPA)和特异性针对PTPA基因序列的RNA干扰质粒pSUPER-siPTPA(siPTPA),分别转染入HEK293/tau细胞系,蛋白免疫印迹技术检测tau蛋白各位点磷酸化水平,检测与tau磷酸化相关的激酶、PP2AC蛋白、PP2AC去甲基化、磷酸化水平的变化。用PP2A活性试剂盒检测转染PP2A活性变化;用细胞免疫荧光观察PTPA与tau的磷酸化位点的细胞共定位;用RT-PCR方法检测PTP1B转录水平变化。
结果:(1) wtPTPA有效地增加了PTPA的表达,pSUP-siPTPA有效地降低了PTPA的表达;(2)293/tau细胞内过表达PTPA可以降低tau磷酸化水平,敲除PTPA使tau蛋白磷酸化水平增加;(3)调控PTPA表达水平可改变PP2A活性,但对GSK-3β没有影响;(4)OA可逆转过表达PTPA后对tau磷酸化水平的降低;(5)过表达PTPA能降低PP2AC Y307磷酸化水平;PTPA敲除后PP2ACY307磷酸化水平升高;(6)过表达PTPA能增加PP2AC Y307位点磷酸酯酶PTP1B的转录和蛋白表达水平;PTPA敲除后PTP1B的转录和蛋白表达水平降低,而其他引起PP2AC Y307变化的激酶没有发生变化。
结论:PTPA调控PTP1B的mRNA和蛋白水平而影响PP2AC307位点酪氨酸磷酸化。
Alzheimer's disease (Alzheimer's disease, AD) is a progressive memory loss and cognitive impairment in neurodegenerative disease, the characteristic pathological changes in the brain is: neurofibrillary tangles (NFT) in neurons and senile plaques (senile plaques, SP). The main component of neurofibrillary tangles is the abnormal phosphorylated tau protein. 107 types of tyrosine phosphatases are in human body; PP2A belongs to PPP family, and plays an important role in tau phosphorylation. PP2A catalytic subunit is regulated by catalytic subunit level and posttranslational modification, for example methylation at Leu309 and phosphorylation at Tyr307. PTPA, exists in animal tissues and cells, could activate PP2A via changing PP2AC space conformation and increasing methylation level at Leu309 by PME. It’s not clear whether PTPA has effects on Tyr307 phosphorylationai level.
Objective: To explore the effects of PTPA on PP2AC Y307 phosphorylational level and the underlying mechanism.
Materials and Methods: PTPA wild type plasmid (wt-PTPA) and siPTPA (pSUPER-siPTPA) were constructed and transfected into HEK293/tau cells. Proteins levels were detected by Western blotting and Immunofluorescence, PP2A actvity was detected by protein phosphatase activity assay kit, RT-PCR was used to deteced PTP1B mRNA.
Results: (1) Overexpression of PTPA reduces tau phosphorylation level, knockdown of PTPA increases tau phosphorylation level; (2) Overexpression of PTPA increases PP2A activity, PTPA knockdown decreases PP2A activity; (3) PTPA regulates PP2AC Y307 phosphorylation and PP2Ac L309 methylation level, but has no obvious effects on other major enzymes which regulate tau phosphorylation; (4) Overexpression of PTPA increases PTP1B mRNA and protein levels; PTPA knockdown decreases PTP1B mRNA and protein levels.
Conclusion: PTPA can regulate PP2AC Y307 phosphorylation level by changing PTP1B mRNA and protein level.
引文
1 Grundke-Iqbal, I., Iqbal, K., Quinlan, M., Tung, Y.C., Zaidi, M.S., Wisniewski, H.M. (1986) Microtubule-associated protein tau: a component of Alzheimer paired helical filament. J. Biol. Chem. 261, 6084-6089.
2 Grundke-Iqbal, I., Iqbal, K., Tung, Y.C., Quinlan, M., Wisniewski, H.M., Binder, L.U.(1986b) Abnormal phosphorylation of the microtubule-associated protein tau(tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U.S.A. 83, 4913-4917.
3 Lee, V.M., Balin, B.J., Otvos, L.J., Trojanowski, J.Q., 1991. A68: a major subunit of the paired helical filaments and derivatized forms of normal tau. Science 251, 675-678.
4 Khatoon, S., Grundke-Iqbal, I., Iqbal, K.(1992) Brain levels of microtubule associated protein tau are elevated in Alzheimer’s disease brain: a radioimmunoslot-blot assay for nanograms of the protein. J. Neurochem. 59, 750-753.
5 Khatoon, S., Grundke-Iqbal, I., Iqbal, K.(1994) Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Lett. 351, 80-84.
6 Deters, N. (2009) Substrate-specific reduction of PP2A activity exaggerates tau pathology. Biochem Biophys Res Commun. 379(2):400-5.
7 Kowluru, A., Metz, S.A. (1996) Carboxylmethylation of the catalytic subunit of protein phosphatase 2A in insulin secreting cells: evidence for functional consequences on enzyme activity and insulin secretion. Endocrinology, 137:2315-2323,
8 Xing Y., Li Z., Chen Y.(2008) Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell,154-163
9 Zhou XW, Gustafsson JA, Tanila H, Bjorkdahl C, Liu R, Winblad B, Pei JJ. (2008) Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A. Neurobiol Dis. 31(3): 386-94.
10 Liu, R., Zhou, X.W., Tanila, H., Bjorkdahl, C., Wang, J.Z, Guan ZZ, Cao Y, Gustafsson JA, Winblad B, Pei JJ. (2008) Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology. J Cell Mol Med. 12(1): 241-257.
11 Liu, R., Pei, J.J.,Wang, X.C., Zhou, X.W., Tian, Q.,Winblad, B.,Wang, J.Z., (2005c). Acute anoxia induces tau dephosphorylation in rat brain slices and its possible underlying mechanisms. J. Neurochem. 94, 1225-1234.
12 Wang, J.Z., Gong, C.X., Zaidi, T., Grundke-Iqbal, I., Iqbal, K. (1995). Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J. Biol.Chem. 270, 4854-4860.
13 Wang, J.Z., Wu, Q., Smith, A., Grundke-Iqbal, I., Iqbal, K. (1998). Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase. FEBS Lett. 436, 28-34.
14 Xu, Y., Xing, Y., Chen, Y. (2006). Structure of the protein phosphatase2A holoenzyme. Cell. (6): 1239-1251
15 Kim, D., Su, J., Cotman, C.W. (1999). Sequence of neurodegeneration andaccumulation of phosphorylated tau in cultured neurons after okadaic acid treatment. Brain Res. 839, 253-262.5535-5544.
16 Gong, C.X., Singh, T.J., Grundke-Igbal, I., Igbal, K. (1993). Phosphoprotein phosphatase activities in Alzheimer disease brain. J. Neurochem. 61, 921-927.
17 Gong, C.X., Weigiel, J., Lidsky, T., Zuck, L., Avila, J., Wisniewski, H.M., Grundke-Iqbal, I., Iqbal, K. (2000b). Regulation of phosphorylation of neuronal microtubule-associated proteins MAP1b and MAP2 by protein phosphatase-2A and -2B in rat brain. Brain Res. 853, 299-309.
18 Pei, J.J., Sersen, E., Iqbal, K., Grundke-Iqbal, I. (1994). Expression of protein phosphatases (PP-1, PP-2A, PP-2B and PTP-1B) and protein kinases (MAP kinase and P34cdc2) in the hippocampus of patients with Alzheimer disease and normal aged individuals. Brain Res. 655,70-76.
19 Liu, F., Grundke-Iqbal, I., Iqbal, K., Gong, C.X. (2005). Contributions of proteinphosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur. J. Neurosci. 22, 1942-1950.
20 Gong, C.X., Liu, F.,Wu, G., Rossie, S.,Wegiel, J., Li, L., Grundke-Iqbal, I., Iqbal, K. (2004).Dephosphorylation of microtubule-associated protein tau by protein phospha-tase 5. J. Neurochem. 88, 298-310.
21 Gong, C.X., Lidsky, T., Wegiel, J., Zuck, L., Grundke-Iqbal, I., Iqbal, K. (2000). Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J. Biol. Chem. 275, 5535-5544。
22 Planel, E., Yasutake, K., Fujita, S.C., Ishiguro, K. (2001). Inhibition of phosphatase 2A overrides tau protein kinase 1/glycogen synthase kinase3 and cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse. J. Biol. Chem. 276, 34298-34306.
23 Wang, J.Z., Gong, C.X., Zaidi, T., Grundke-Iqbal, I., Iqbal, K., 1995. Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J. Biol. Chem. 270, 4854-4860.
24 Cayla, X., Merlevede,W. (1990). Isolation and characterization of a tyrosyl phosphatase activator from rabbit skeletal muscle and Xenopus laevis ocytes. Biochemistry. 29, 633-642.
24 Cayla, X., Goris, J., Hermann, J., Hendrix, P., Ozon, R. and Merlevede, W. (1990) Isolation and characterization of a tyrosyl phosphatase activator from rabbit skeletal muscle andXenopus laevis oocytes. Biochemistry. 29, 658-667
25 Cayla, X., Goris, J. (1994). Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A. J. Biol. Chem. 269, 15668-15675.
26 Christine Van Hoof, Belgium. (1994) The phosphotyrosyl phosphatase activator of protein phosphatase 2A,A novel purification method, immunological and enzymic characterization. J.Biol.Chem. 226, 899-907
27 Patrizia Agostinia, Arianna, Donelladeana., Christine., Van, Hoof., Jozef, Goris. (1996). A comparative study of the phosphotyrosyl phosphatase specificity ofprotein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins pSO/HSl, c-Fgr and LynEur. J.Biol.Chem. 236. 548-557
28 Veerle , Janssens, Christine, V .H., Ivo De Baere, Wilfried Merlevede, and Jozef, Goris. (2000). The Phosphotyrosyl Phosphatase Activator Gene Is a Novel p53 Target Gene. J.Biol.Chem. 275. 20488-20495,
29 Thomas, Fellner., Daniel, H., Egon Ogris.( 2003) A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo. Genes Development. 17:2138-2150
30 Jordens, J., Van Hoof, C. (2006). The protein phosphatase 2A phosphatase activator is a novel peptidyl-prolyl cis/trans-isomerase. J.Biol.Chem. 281, 6349-6357.
31 Longin, S., Van Hoof, C. (2004). An inactive protein phosphatase 2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator. J.Biol.Chem. 380, 111-119.
32 Yang, C., Chen Yu., Xu,YH., Philip D. Jeffrey, B. and Shi YG. (2006). Structure and Mechanism of the Phosphotyrosyl Phosphatase Activator. Molecular Cell. 23, 535-546
33 Audur, Magnusdottir., Stenmark., Susanne, Flodin., Tomas, Nyman.,Martin, Hammarstro.,Maria, Ehn., MAmin, Bakali H., Helena, Berglund., and Pa Nordlund. (2006). The Crystal Structure of a Human PP2A Phosphatase Activator Reveals a Novel Foldand Highly Conserved Cleft Implicated in Protein-Protein Interactions. J.Biol.Chem. 281.22434-22438.
34 Sonish, Azam., Elliot, Drobetsky., Dindial, Ramotar.(2007). Overexpression of the cis/trans isomerase PTPA triggers caspase3-dependent apoptosis. Apoptosis. 12:1243-1255
35 Gong, C.X., Singh, T.J., Grundke-Igbal, I., Igbal, K. (1993). Phosphoprotein Phosphatase activities in Alzheimer disease brain. J. Neurochem. 61,921-927.
36 Xie, H., Litersky, J.M., Hartigan, J.A., Jope, R.S. (1998). The interrelationship between selective tau phosphorylation and microtubule association. Brain Res.798, 173-183.
37 Janssens, V. and Goris, J. (2001). Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. J.Biol.Chem. 353,417-439
38 Sontag E. (2001). Protein phosphatase 2A: the trojan horse of cellular signaling. Celluar Signalling. (1): 7-16
39 Cho,U.S., Xu,W. (2007) Crystal structure of a protein phosphatase 2A heterotrimer ic holoenzyme. Nature. 445, 53-57.
40 Foulkes, J.G., Erikson, E., Erikson, R.L. (1983) Separation of multiple phosphotyrosyl-and phosphoseryl-protein phosphatases from chicken brain. J.Biol.Chem. 258:431-438
41 Alonso, A., Mustelin, T. (2004). Protein tyrosine phosphatases in the human genome. Cell. 117,699-711.
42 Chatfield, K., Eastman, A. (2004) Inhibitors of protein phosphatases1 and 2A differentially prevent intrinsic and extrinsic apoptosis pathways. Biochem Biophys Res Commun 323:1313-1320 [43 Planel, E., Yasutake, K., Fujita, S.C., Ishiguro, K. (2001). Inhibition of phosphatase 2A overrides tau protein kinase 1/glycogen synthase kinase-3βand cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse. J.Biol.Chem. 276,34298-34306.
44 Bennecib, M., Gong, C.X., Grundke-Iqbal, I., Iqbal, K. (2001). Inhibition of PP-2A up-regulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser262/356. FEBS Lett. 490, 15-22.
45 Saito, T., Ishiguro, K., Uchida, T., Miyamoto, E., Kishimoto, T., Hisanaga, S., (1995). Insitu dephosphorylation of tau by protein phosphatase 2A and 2B in fetal rat primary cultured neurons. FEBS Lett. 376. 238-242.
46 Wada, T., Penninger, J.M. (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene. 23:2838-2849
47. Chen, J., Martin, B.L., Brautigan, D.L. (1992). Regulation ofprotein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science.257:1261-1274.
48. Chen, J., Parsons, S., Brautigan, D.L. (1994) Tyrosine phosphorylation of protein phosphatase 2A in response to growth stimulation and v-src transformation of fibroblasts. J.Biol.Chem. 269: 7957-7962.
49 Agostinis, P., Goris, J. (1996). A comparative study of the phosphotyrosyl phosphatase specificity of protein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins p50/HS1, c-Fgr and Lyn. Eur. J.Biol.Chem. 236, 548-557.
1 Grundke-Iqbal, Binder, L.U.(1986b). Abnormal phosphorylation of the microtubule-associated protein tau(tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U.S.A. 83, 4913-4917.
2 Khatoon, S., Grundke-Iqbal, I., Iqbal, K.(1992). Brain levels ofmicrotubule associated protein tau are elevated in Alzheimer’s disease brain: a radioimmunoslot-blot assay for nanograms of the protein. J. Neurochem. 59, 750-753.
3 Khatoon, S., Grundke-Iqbal, I., Iqbal, K., 1994. Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Lett. 351, 80-84。
4 Treiber, K.A., Lyketsos, C.G., Corcoran, C. (2008) Vascular factors and risk for neuropsychiatric symptoms in Alzheimer's disease:the Cache County Study. Int Psychogeriatr. 20:538?553.
5 Li, H.L., Wang, H.H., Liu, S.J., Deng, Y.Q., Zhang, Y.J., Tian, Q., Wang, X.C., Chen, X.Q.,Yang, Y., Zhang, J.Y.,Wang, Q., Xu,H., Liao, F.F.,Wang, J.Z. (2007). Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, amechanisminvolved in Alzheimer’s neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 104, 3591–3596
6 Grundke-Iqbal, I., Iqbal, K., Quinlan, M., Tung, Y.C., Zaidi, M.S., Wisniewski, H.M. (1986) Microtubule-associated protein tau: a component of Alzheimer paired helical filament. J. Biol. Chem. 261, 6084-6089.
7 Lee, V.M., Balin, B.J., Otvos, L.J., Trojanowski, J.Q. (1991). A68: a major subunit of the paired helical filaments and derivatized forms of normal tau. Science. 251, 675-678.
8 Xie, H., Litersky, J.M., Hartigan, J.A., Jope, R.S. (1998). The interrelationship between selective tau phosphorylation and microtubule association. Brain Res. 798, 173-183.
9 Janssens, V. and Goris, J.( 2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem. J. 353,417-439
10 Deters, N. (2009). Substrate-specific reduction of PP2A activity exaggerates tau pathology. Biochem Biophys Res Commun. 379(2):400-5. Epub. 2009 Jan 4.)
11 Ishiquro, K., Imahori, K. (1993). Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett. 325, 167-172.
12 Sontag, E., Hladik, C., Montgomery, L., Luangpirom A, et al. (2004) Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. J Neuropathol Exp Neurol. 63(10):1080-91.
13 Xu, Y., Xing, Y., Chen, Y. (2006). Structure of the protein phosphatase2A holoenzyme. Cell. (6): 1239-1251
14 Cho, U.S., Xu,W. (2007) Crystal structure of a protein phosphatase 2A heterotrimer ic holoenzyme. Nature. 445, 53–57.
15 Wang, J.Z., Gong, C.X., Zaidi, T., Grundke-Iqbal, I., Iqbal, K. (1995). Dephosphorylationof Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J. Biol.Chem. 270, 4854-4860.
16 Gong, C.X., Liu, F.,Wu, G., Rossie, S.,Wegiel, J., Li, L., Grundke-Iqbal, I., Iqbal, K. (2004). Dephosphorylation of microtubule-associated protein tau by protein phospha-tase 5. J. Neurochem. 88, 298–310.
17 Gong, C.X., Lidsky, T., Wegiel, J., Zuck, L., Grundke-Iqbal, I., Iqbal, K. (2000). Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J. Biol. Chem. 275, 5535–5544。
18 Steinbrecher, K.A. (2005). Glycogensynthase kinase 3βfunctions to specify gene2s pecific, NF2κB2 de2pendent transcri ption. Mol Cell Biol. 25 ( 19 ) :8444 - 8455.
19 Ali, A., Hoeflich, K.P., Woodgett, J.R. (2001). Glycogen synthase kinase-3 : properties, function, and regulati on. Chem Rev. 101 (8) : 2527 - 2540.
20 Sanchez., Fueyo, A., Tian, J., Picarella D. (2003). Tim23 inhibits Thelper type 12 mediated auto2 and alloimmune res ponses and promotes immunol ogical tolerance. N at Immunol. 4(11) : 1093-1111.
21 Graves, P.E., Siroux, V., Guerra, S. (2005) Associati on of atopy and eczema with polymor phisms in T2 cell i mmunoglobulin domain and mucin domain inducible T2 cell kinase gene cluster in chrosmosome 5q33. J Allergy Clin Imm unol 116 ( 3 ) :650-656.
22 Liu, R., Pei, J.J.,Wang, X.C., Zhou, X.W., Tian, Q.,Winblad, B.,Wang, J.Z., (2005c). Acute anoxia induces tau dephosphorylation in rat brain slices and its possible underlying mechanisms. J. Neurochem. 94, 1225-1234.
23 Arino, J. and Johnson, G..L. (1988). Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes. Proc. Natl. Acad. Sci. USA. 85, 4252-4256.
24 Sontag, E. (2001). Protein phosphatase 2A: the trojan horse of cellular signaling. Celluar Signalling. (1): 7-16
25 Chen, J., Martin, B.L., Brautigan, D.L. (1992). Regulation of protein serine–threonine phosphatase type-2A by tyrosine phosphorylation, Science. 257 1261-1264.
26 Janssens, V., Goris, J.(2001). Protein phosphatase 2A: a highly regulated family serine/thr eonine phosphatases implicated in cell growth and signalling. Biochemical J. (3): 417-439
27 Bennecib, M., Gong, C.X., Grundke-Iqbal, I., Iqbal, K.(2001). Inhibition of PP-2A up-regulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser262/356. FEBS Lett. 490, 15-22.
28 Xing, Y., Li, Z., Chen, Y. (2008). Structural mechanism of demethylation and inactivatio n of protein phosphatase 2A.. Cell. (1):154 163
29 Schild, A., Ittner, L.M., Gotz, J. (2006). Altered phosphorylation of cytoskeletal proteins in mutant protein phosphatase 2A transgenic mice. Biochem.Biophys.Res. Commun. 343, 1171-1178。
30 Holm, L., Sander, C. (1993). Protein structure comparison by alignment of distance matrices. J. Mol. Biol. 233, 123-138.
31 Lee, J., Chen, Y., Tolstykh, T., Stock, J. (1996) A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Proc Natl Acad Sci USA 93:6043-6047
32 Kowluru, A., Metz, S.A. (1996) Carboxylmethylation of the catalytic subunit of protein phosphatase 2A in insulin secreting cells: evidence for functional consequences on enzyme activity and insulin secretion. Endocrinology 137:2315-2323,
33 Xing, Y., Li, Z., Chen, Y. (2008). Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell. 154-163
34 Zhou, X.W., Gustafsson, J.A, Tanila, H., Bjorkdahl, C., Liu, R., Winblad, B., Pei, J.J. (2008) Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A. Neurobiol Dis. 31(3): 386-94.
35 Liu, R, Zhou, X.W, Tanila, H., Bjorkdahl, C., Wang, J.Z, Guan, Z.Z., Cao, Y., Gustafsson, J.A., Winblad, B., Pei, J.J. (2008) Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology. J Cell Mol Med. 12(1): 241-257.
36 Chen, J. , Parsons, S. , Brautigan, D.L. (1992). Tyrosine phosphorylation of protein phosphatase 2A in response to growth stimulation and v-src transformation of fibroblasts. J. Biol. Chem. 269 503-511.
37 Chen, J., Parsons, S, Brautigan, D.L. (1994) Tyrosine phosphorylation of protein phosphatase 2A in response to growth stimulation and v-src transformation of fibroblasts. J Biol Chem. 269: 7957-7962.
38 Agostinis, P., Goris, J. (1996). A comparative study of the phosphotyrosyl phosphatase specificity of protein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins p50/HS1, c-Fgr and Lyn. Eur. J. Biochem. 236, 548-557.
39 Cayla, X., Goris, J., Hermann, J., Hendrix, P., Ozon, R. and Merlevede, W.(1990) Isolation and characterization of a tyrosyl phosphatase activator from rabbit skeletal muscle andXenopus laevis oocytes. Biochemistry. 29, 658-667
40 Cayla, X., Goris, J. (1994). Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A. J. Biol. Chem. 269, 15668-15675.
41 Christine Van Hoof, Belgium. (1994) The phosphotyrosyl phosphatase activator of protein phosphatase 2A,A novel purification method, immunological and enzymic characterization. J. Biochem. 226, 899-907
42 Patrizia Agostinia, Arianna Donelladeana, Christine Van Hoof, Jozef Goris. (1996). A comparative study of the phosphotyrosyl phosphatase specificity of protein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins pSO/HSl, c-Fgr and LynEur. J. Biochem. 236. 548-557
43 Veerle Janssens, Christine Van Hoof, Ivo De Baere, Wilfried Merlevede, and Jozef Goris. (2000). The Phosphotyrosyl Phosphatase Activator Gene Is a Novel p53 Target Gene. J. Biochem. 275. 20488-20495,
44 Thomas Fellner, Daniel H. Lackner,Hans Hombauer,PatrickPiribauer, Ingrid Mudrak, Katrin Zaragoza, Claudia Juno, and Egon Ogris.( 2003) A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo. Genes Development. 17:2138-2150
45 Jordens, J., Van Hoof, C. (2006). The protein phosphatase 2A phosphatase activator is a novel peptidyl-prolyl cis/trans-isomerase. J.Biol.Chem. 281, 6349-6357.
46 Longin, S., Van Hoof, C. (2004). An inactive protein phosphatase 2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator. Biochem. J. 380, 111-119.
47 Yang, C., Xing, YN., Chen, Y., Xu,YH., Lin, Z., Li,Z., Philip, D., Shi, YG. (2006). Structure and Mechanism of the Phosphotyrosyl Phosphatase Activator. Molecular Cell. 23, 535-546
48 AudurMagnusdottir, Stenmark, Susanne Flodin,Tomas Nyman,MartinHammarstro,Maria Ehn,MAmin Bakali H, Helena Berglund, and Pa Nordlund. (2006). The Crystal Structure of a Human PP2A Phosphatase Activator Reveals a Novel Foldand Highly Conserved Cleft Implicated in Protein-Protein Interactions. Biochem. J. 281.22434-22438.
49 Sonish Azam ., Elliot Drobetsky., Dindial Ramotar.(2007). Overexpression of the cis/trans isomerase PTPA triggers caspase3-dependent apoptosis. Apoptosis. 12:1243-1255
2 Grundke-Iqbal, I., Iqbal, K., Tung, Y.C., Quinlan, M., Wisniewski, H.M., Binder, L.U.(1986b) Abnormal phosphorylation of the microtubule-associated protein tau(tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U.S.A. 83, 4913-4917.
3 Lee, V.M., Balin, B.J., Otvos, L.J., Trojanowski, J.Q., 1991. A68: a major subunit of the paired helical filaments and derivatized forms of normal tau. Science 251, 675-678.
4 Khatoon, S., Grundke-Iqbal, I., Iqbal, K.(1992) Brain levels of microtubule associated protein tau are elevated in Alzheimer’s disease brain: a radioimmunoslot-blot assay for nanograms of the protein. J. Neurochem. 59, 750-753.
5 Khatoon, S., Grundke-Iqbal, I., Iqbal, K.(1994) Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Lett. 351, 80-84.
6 Deters, N. (2009) Substrate-specific reduction of PP2A activity exaggerates tau pathology. Biochem Biophys Res Commun. 379(2):400-5.
7 Kowluru, A., Metz, S.A. (1996) Carboxylmethylation of the catalytic subunit of protein phosphatase 2A in insulin secreting cells: evidence for functional consequences on enzyme activity and insulin secretion. Endocrinology, 137:2315-2323,
8 Xing Y., Li Z., Chen Y.(2008) Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell,154-163
9 Zhou XW, Gustafsson JA, Tanila H, Bjorkdahl C, Liu R, Winblad B, Pei JJ. (2008) Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A. Neurobiol Dis. 31(3): 386-94.
10 Liu, R., Zhou, X.W., Tanila, H., Bjorkdahl, C., Wang, J.Z, Guan ZZ, Cao Y, Gustafsson JA, Winblad B, Pei JJ. (2008) Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology. J Cell Mol Med. 12(1): 241-257.
11 Liu, R., Pei, J.J.,Wang, X.C., Zhou, X.W., Tian, Q.,Winblad, B.,Wang, J.Z., (2005c). Acute anoxia induces tau dephosphorylation in rat brain slices and its possible underlying mechanisms. J. Neurochem. 94, 1225-1234.
12 Wang, J.Z., Gong, C.X., Zaidi, T., Grundke-Iqbal, I., Iqbal, K. (1995). Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J. Biol.Chem. 270, 4854-4860.
13 Wang, J.Z., Wu, Q., Smith, A., Grundke-Iqbal, I., Iqbal, K. (1998). Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase. FEBS Lett. 436, 28-34.
14 Xu, Y., Xing, Y., Chen, Y. (2006). Structure of the protein phosphatase2A holoenzyme. Cell. (6): 1239-1251
15 Kim, D., Su, J., Cotman, C.W. (1999). Sequence of neurodegeneration andaccumulation of phosphorylated tau in cultured neurons after okadaic acid treatment. Brain Res. 839, 253-262.5535-5544.
16 Gong, C.X., Singh, T.J., Grundke-Igbal, I., Igbal, K. (1993). Phosphoprotein phosphatase activities in Alzheimer disease brain. J. Neurochem. 61, 921-927.
17 Gong, C.X., Weigiel, J., Lidsky, T., Zuck, L., Avila, J., Wisniewski, H.M., Grundke-Iqbal, I., Iqbal, K. (2000b). Regulation of phosphorylation of neuronal microtubule-associated proteins MAP1b and MAP2 by protein phosphatase-2A and -2B in rat brain. Brain Res. 853, 299-309.
18 Pei, J.J., Sersen, E., Iqbal, K., Grundke-Iqbal, I. (1994). Expression of protein phosphatases (PP-1, PP-2A, PP-2B and PTP-1B) and protein kinases (MAP kinase and P34cdc2) in the hippocampus of patients with Alzheimer disease and normal aged individuals. Brain Res. 655,70-76.
19 Liu, F., Grundke-Iqbal, I., Iqbal, K., Gong, C.X. (2005). Contributions of proteinphosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur. J. Neurosci. 22, 1942-1950.
20 Gong, C.X., Liu, F.,Wu, G., Rossie, S.,Wegiel, J., Li, L., Grundke-Iqbal, I., Iqbal, K. (2004).Dephosphorylation of microtubule-associated protein tau by protein phospha-tase 5. J. Neurochem. 88, 298-310.
21 Gong, C.X., Lidsky, T., Wegiel, J., Zuck, L., Grundke-Iqbal, I., Iqbal, K. (2000). Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J. Biol. Chem. 275, 5535-5544。
22 Planel, E., Yasutake, K., Fujita, S.C., Ishiguro, K. (2001). Inhibition of phosphatase 2A overrides tau protein kinase 1/glycogen synthase kinase3 and cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse. J. Biol. Chem. 276, 34298-34306.
23 Wang, J.Z., Gong, C.X., Zaidi, T., Grundke-Iqbal, I., Iqbal, K., 1995. Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J. Biol. Chem. 270, 4854-4860.
24 Cayla, X., Merlevede,W. (1990). Isolation and characterization of a tyrosyl phosphatase activator from rabbit skeletal muscle and Xenopus laevis ocytes. Biochemistry. 29, 633-642.
24 Cayla, X., Goris, J., Hermann, J., Hendrix, P., Ozon, R. and Merlevede, W. (1990) Isolation and characterization of a tyrosyl phosphatase activator from rabbit skeletal muscle andXenopus laevis oocytes. Biochemistry. 29, 658-667
25 Cayla, X., Goris, J. (1994). Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A. J. Biol. Chem. 269, 15668-15675.
26 Christine Van Hoof, Belgium. (1994) The phosphotyrosyl phosphatase activator of protein phosphatase 2A,A novel purification method, immunological and enzymic characterization. J.Biol.Chem. 226, 899-907
27 Patrizia Agostinia, Arianna, Donelladeana., Christine., Van, Hoof., Jozef, Goris. (1996). A comparative study of the phosphotyrosyl phosphatase specificity ofprotein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins pSO/HSl, c-Fgr and LynEur. J.Biol.Chem. 236. 548-557
28 Veerle , Janssens, Christine, V .H., Ivo De Baere, Wilfried Merlevede, and Jozef, Goris. (2000). The Phosphotyrosyl Phosphatase Activator Gene Is a Novel p53 Target Gene. J.Biol.Chem. 275. 20488-20495,
29 Thomas, Fellner., Daniel, H., Egon Ogris.( 2003) A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo. Genes Development. 17:2138-2150
30 Jordens, J., Van Hoof, C. (2006). The protein phosphatase 2A phosphatase activator is a novel peptidyl-prolyl cis/trans-isomerase. J.Biol.Chem. 281, 6349-6357.
31 Longin, S., Van Hoof, C. (2004). An inactive protein phosphatase 2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator. J.Biol.Chem. 380, 111-119.
32 Yang, C., Chen Yu., Xu,YH., Philip D. Jeffrey, B. and Shi YG. (2006). Structure and Mechanism of the Phosphotyrosyl Phosphatase Activator. Molecular Cell. 23, 535-546
33 Audur, Magnusdottir., Stenmark., Susanne, Flodin., Tomas, Nyman.,Martin, Hammarstro.,Maria, Ehn., MAmin, Bakali H., Helena, Berglund., and Pa Nordlund. (2006). The Crystal Structure of a Human PP2A Phosphatase Activator Reveals a Novel Foldand Highly Conserved Cleft Implicated in Protein-Protein Interactions. J.Biol.Chem. 281.22434-22438.
34 Sonish, Azam., Elliot, Drobetsky., Dindial, Ramotar.(2007). Overexpression of the cis/trans isomerase PTPA triggers caspase3-dependent apoptosis. Apoptosis. 12:1243-1255
35 Gong, C.X., Singh, T.J., Grundke-Igbal, I., Igbal, K. (1993). Phosphoprotein Phosphatase activities in Alzheimer disease brain. J. Neurochem. 61,921-927.
36 Xie, H., Litersky, J.M., Hartigan, J.A., Jope, R.S. (1998). The interrelationship between selective tau phosphorylation and microtubule association. Brain Res.798, 173-183.
37 Janssens, V. and Goris, J. (2001). Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. J.Biol.Chem. 353,417-439
38 Sontag E. (2001). Protein phosphatase 2A: the trojan horse of cellular signaling. Celluar Signalling. (1): 7-16
39 Cho,U.S., Xu,W. (2007) Crystal structure of a protein phosphatase 2A heterotrimer ic holoenzyme. Nature. 445, 53-57.
40 Foulkes, J.G., Erikson, E., Erikson, R.L. (1983) Separation of multiple phosphotyrosyl-and phosphoseryl-protein phosphatases from chicken brain. J.Biol.Chem. 258:431-438
41 Alonso, A., Mustelin, T. (2004). Protein tyrosine phosphatases in the human genome. Cell. 117,699-711.
42 Chatfield, K., Eastman, A. (2004) Inhibitors of protein phosphatases1 and 2A differentially prevent intrinsic and extrinsic apoptosis pathways. Biochem Biophys Res Commun 323:1313-1320 [43 Planel, E., Yasutake, K., Fujita, S.C., Ishiguro, K. (2001). Inhibition of phosphatase 2A overrides tau protein kinase 1/glycogen synthase kinase-3βand cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse. J.Biol.Chem. 276,34298-34306.
44 Bennecib, M., Gong, C.X., Grundke-Iqbal, I., Iqbal, K. (2001). Inhibition of PP-2A up-regulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser262/356. FEBS Lett. 490, 15-22.
45 Saito, T., Ishiguro, K., Uchida, T., Miyamoto, E., Kishimoto, T., Hisanaga, S., (1995). Insitu dephosphorylation of tau by protein phosphatase 2A and 2B in fetal rat primary cultured neurons. FEBS Lett. 376. 238-242.
46 Wada, T., Penninger, J.M. (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene. 23:2838-2849
47. Chen, J., Martin, B.L., Brautigan, D.L. (1992). Regulation ofprotein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science.257:1261-1274.
48. Chen, J., Parsons, S., Brautigan, D.L. (1994) Tyrosine phosphorylation of protein phosphatase 2A in response to growth stimulation and v-src transformation of fibroblasts. J.Biol.Chem. 269: 7957-7962.
49 Agostinis, P., Goris, J. (1996). A comparative study of the phosphotyrosyl phosphatase specificity of protein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins p50/HS1, c-Fgr and Lyn. Eur. J.Biol.Chem. 236, 548-557.
1 Grundke-Iqbal, Binder, L.U.(1986b). Abnormal phosphorylation of the microtubule-associated protein tau(tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U.S.A. 83, 4913-4917.
2 Khatoon, S., Grundke-Iqbal, I., Iqbal, K.(1992). Brain levels ofmicrotubule associated protein tau are elevated in Alzheimer’s disease brain: a radioimmunoslot-blot assay for nanograms of the protein. J. Neurochem. 59, 750-753.
3 Khatoon, S., Grundke-Iqbal, I., Iqbal, K., 1994. Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Lett. 351, 80-84。
4 Treiber, K.A., Lyketsos, C.G., Corcoran, C. (2008) Vascular factors and risk for neuropsychiatric symptoms in Alzheimer's disease:the Cache County Study. Int Psychogeriatr. 20:538?553.
5 Li, H.L., Wang, H.H., Liu, S.J., Deng, Y.Q., Zhang, Y.J., Tian, Q., Wang, X.C., Chen, X.Q.,Yang, Y., Zhang, J.Y.,Wang, Q., Xu,H., Liao, F.F.,Wang, J.Z. (2007). Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, amechanisminvolved in Alzheimer’s neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 104, 3591–3596
6 Grundke-Iqbal, I., Iqbal, K., Quinlan, M., Tung, Y.C., Zaidi, M.S., Wisniewski, H.M. (1986) Microtubule-associated protein tau: a component of Alzheimer paired helical filament. J. Biol. Chem. 261, 6084-6089.
7 Lee, V.M., Balin, B.J., Otvos, L.J., Trojanowski, J.Q. (1991). A68: a major subunit of the paired helical filaments and derivatized forms of normal tau. Science. 251, 675-678.
8 Xie, H., Litersky, J.M., Hartigan, J.A., Jope, R.S. (1998). The interrelationship between selective tau phosphorylation and microtubule association. Brain Res. 798, 173-183.
9 Janssens, V. and Goris, J.( 2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem. J. 353,417-439
10 Deters, N. (2009). Substrate-specific reduction of PP2A activity exaggerates tau pathology. Biochem Biophys Res Commun. 379(2):400-5. Epub. 2009 Jan 4.)
11 Ishiquro, K., Imahori, K. (1993). Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett. 325, 167-172.
12 Sontag, E., Hladik, C., Montgomery, L., Luangpirom A, et al. (2004) Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. J Neuropathol Exp Neurol. 63(10):1080-91.
13 Xu, Y., Xing, Y., Chen, Y. (2006). Structure of the protein phosphatase2A holoenzyme. Cell. (6): 1239-1251
14 Cho, U.S., Xu,W. (2007) Crystal structure of a protein phosphatase 2A heterotrimer ic holoenzyme. Nature. 445, 53–57.
15 Wang, J.Z., Gong, C.X., Zaidi, T., Grundke-Iqbal, I., Iqbal, K. (1995). Dephosphorylationof Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J. Biol.Chem. 270, 4854-4860.
16 Gong, C.X., Liu, F.,Wu, G., Rossie, S.,Wegiel, J., Li, L., Grundke-Iqbal, I., Iqbal, K. (2004). Dephosphorylation of microtubule-associated protein tau by protein phospha-tase 5. J. Neurochem. 88, 298–310.
17 Gong, C.X., Lidsky, T., Wegiel, J., Zuck, L., Grundke-Iqbal, I., Iqbal, K. (2000). Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J. Biol. Chem. 275, 5535–5544。
18 Steinbrecher, K.A. (2005). Glycogensynthase kinase 3βfunctions to specify gene2s pecific, NF2κB2 de2pendent transcri ption. Mol Cell Biol. 25 ( 19 ) :8444 - 8455.
19 Ali, A., Hoeflich, K.P., Woodgett, J.R. (2001). Glycogen synthase kinase-3 : properties, function, and regulati on. Chem Rev. 101 (8) : 2527 - 2540.
20 Sanchez., Fueyo, A., Tian, J., Picarella D. (2003). Tim23 inhibits Thelper type 12 mediated auto2 and alloimmune res ponses and promotes immunol ogical tolerance. N at Immunol. 4(11) : 1093-1111.
21 Graves, P.E., Siroux, V., Guerra, S. (2005) Associati on of atopy and eczema with polymor phisms in T2 cell i mmunoglobulin domain and mucin domain inducible T2 cell kinase gene cluster in chrosmosome 5q33. J Allergy Clin Imm unol 116 ( 3 ) :650-656.
22 Liu, R., Pei, J.J.,Wang, X.C., Zhou, X.W., Tian, Q.,Winblad, B.,Wang, J.Z., (2005c). Acute anoxia induces tau dephosphorylation in rat brain slices and its possible underlying mechanisms. J. Neurochem. 94, 1225-1234.
23 Arino, J. and Johnson, G..L. (1988). Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes. Proc. Natl. Acad. Sci. USA. 85, 4252-4256.
24 Sontag, E. (2001). Protein phosphatase 2A: the trojan horse of cellular signaling. Celluar Signalling. (1): 7-16
25 Chen, J., Martin, B.L., Brautigan, D.L. (1992). Regulation of protein serine–threonine phosphatase type-2A by tyrosine phosphorylation, Science. 257 1261-1264.
26 Janssens, V., Goris, J.(2001). Protein phosphatase 2A: a highly regulated family serine/thr eonine phosphatases implicated in cell growth and signalling. Biochemical J. (3): 417-439
27 Bennecib, M., Gong, C.X., Grundke-Iqbal, I., Iqbal, K.(2001). Inhibition of PP-2A up-regulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser262/356. FEBS Lett. 490, 15-22.
28 Xing, Y., Li, Z., Chen, Y. (2008). Structural mechanism of demethylation and inactivatio n of protein phosphatase 2A.. Cell. (1):154 163
29 Schild, A., Ittner, L.M., Gotz, J. (2006). Altered phosphorylation of cytoskeletal proteins in mutant protein phosphatase 2A transgenic mice. Biochem.Biophys.Res. Commun. 343, 1171-1178。
30 Holm, L., Sander, C. (1993). Protein structure comparison by alignment of distance matrices. J. Mol. Biol. 233, 123-138.
31 Lee, J., Chen, Y., Tolstykh, T., Stock, J. (1996) A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Proc Natl Acad Sci USA 93:6043-6047
32 Kowluru, A., Metz, S.A. (1996) Carboxylmethylation of the catalytic subunit of protein phosphatase 2A in insulin secreting cells: evidence for functional consequences on enzyme activity and insulin secretion. Endocrinology 137:2315-2323,
33 Xing, Y., Li, Z., Chen, Y. (2008). Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell. 154-163
34 Zhou, X.W., Gustafsson, J.A, Tanila, H., Bjorkdahl, C., Liu, R., Winblad, B., Pei, J.J. (2008) Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A. Neurobiol Dis. 31(3): 386-94.
35 Liu, R, Zhou, X.W, Tanila, H., Bjorkdahl, C., Wang, J.Z, Guan, Z.Z., Cao, Y., Gustafsson, J.A., Winblad, B., Pei, J.J. (2008) Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology. J Cell Mol Med. 12(1): 241-257.
36 Chen, J. , Parsons, S. , Brautigan, D.L. (1992). Tyrosine phosphorylation of protein phosphatase 2A in response to growth stimulation and v-src transformation of fibroblasts. J. Biol. Chem. 269 503-511.
37 Chen, J., Parsons, S, Brautigan, D.L. (1994) Tyrosine phosphorylation of protein phosphatase 2A in response to growth stimulation and v-src transformation of fibroblasts. J Biol Chem. 269: 7957-7962.
38 Agostinis, P., Goris, J. (1996). A comparative study of the phosphotyrosyl phosphatase specificity of protein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins p50/HS1, c-Fgr and Lyn. Eur. J. Biochem. 236, 548-557.
39 Cayla, X., Goris, J., Hermann, J., Hendrix, P., Ozon, R. and Merlevede, W.(1990) Isolation and characterization of a tyrosyl phosphatase activator from rabbit skeletal muscle andXenopus laevis oocytes. Biochemistry. 29, 658-667
40 Cayla, X., Goris, J. (1994). Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A. J. Biol. Chem. 269, 15668-15675.
41 Christine Van Hoof, Belgium. (1994) The phosphotyrosyl phosphatase activator of protein phosphatase 2A,A novel purification method, immunological and enzymic characterization. J. Biochem. 226, 899-907
42 Patrizia Agostinia, Arianna Donelladeana, Christine Van Hoof, Jozef Goris. (1996). A comparative study of the phosphotyrosyl phosphatase specificity of protein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins pSO/HSl, c-Fgr and LynEur. J. Biochem. 236. 548-557
43 Veerle Janssens, Christine Van Hoof, Ivo De Baere, Wilfried Merlevede, and Jozef Goris. (2000). The Phosphotyrosyl Phosphatase Activator Gene Is a Novel p53 Target Gene. J. Biochem. 275. 20488-20495,
44 Thomas Fellner, Daniel H. Lackner,Hans Hombauer,PatrickPiribauer, Ingrid Mudrak, Katrin Zaragoza, Claudia Juno, and Egon Ogris.( 2003) A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo. Genes Development. 17:2138-2150
45 Jordens, J., Van Hoof, C. (2006). The protein phosphatase 2A phosphatase activator is a novel peptidyl-prolyl cis/trans-isomerase. J.Biol.Chem. 281, 6349-6357.
46 Longin, S., Van Hoof, C. (2004). An inactive protein phosphatase 2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator. Biochem. J. 380, 111-119.
47 Yang, C., Xing, YN., Chen, Y., Xu,YH., Lin, Z., Li,Z., Philip, D., Shi, YG. (2006). Structure and Mechanism of the Phosphotyrosyl Phosphatase Activator. Molecular Cell. 23, 535-546
48 AudurMagnusdottir, Stenmark, Susanne Flodin,Tomas Nyman,MartinHammarstro,Maria Ehn,MAmin Bakali H, Helena Berglund, and Pa Nordlund. (2006). The Crystal Structure of a Human PP2A Phosphatase Activator Reveals a Novel Foldand Highly Conserved Cleft Implicated in Protein-Protein Interactions. Biochem. J. 281.22434-22438.
49 Sonish Azam ., Elliot Drobetsky., Dindial Ramotar.(2007). Overexpression of the cis/trans isomerase PTPA triggers caspase3-dependent apoptosis. Apoptosis. 12:1243-1255