脑红蛋白对神经元突起生长的作用及其潜在机制
摘要
在中枢神经系统中，神经元突起生长对神经回路和突触连接的建立是必不可少的。诱导神经元突起生长对于中风、神经退行性疾病、外伤性中枢神经系统损伤等疾病的治疗十分重要但却十分困难。神经元成熟后失去产生突起的能力，衰老神经元突起再生尤其困难。因此，为了寻找有效的药物或改进治疗手段来治疗神经系统疾病，必需清楚地了解调节突起生长的分子机制。
脑红蛋白（neuroglobin，Ngb）作为一个具有高氧亲和力的组织珠蛋白，在脊椎动物中枢和周围神经系统的神经元中广泛并特异性表达。在过去大量的研究表明Ngb高表达对缺氧/缺血诱导的神经元损伤及脑缺血动物模型具有保护作用。迄今为止，国内外还未见有关Ngb与神经元突起生长相关性的报道。
本研究采用小鼠成神经瘤N2a细胞系和原代皮层神经元作为实验材料和研究对象，利用细胞培养、分子生物学、免疫印迹和细胞形态学等研究技术和方法，进一步探讨了Ngb对神经元突起生长的作用及其潜在的分子机制。
在小鼠成神经瘤N2a细胞中，采用RNA干扰技术抑制Ngb内源性表达后细胞呈现出显著的突起缺陷表型。反之，过表达Ngb后Ngb基因编码的蛋白表达量增加，神经元的突起明显增长。我们进一步在原代培养的大鼠大脑皮层神经元中发现，随神经元发育，突起的增长，Ngb基因表达量显著增加，而脑红蛋白的同源基因细胞红蛋白（cytoglobin,Cygb）的基因表达没有变化。在原代培养的大鼠大脑皮层神经元中过表达Ngb神经元的突起明显增长。反之，抑制原代培养的大鼠大脑皮层神经元中内源性Ngb的表达，神经细胞的突起与对照组相比明显变短。药理学研究发现在原代皮层神经元中Ngb促进突起生长的作用依赖于Akt及p38MAPK蛋白的活性。我们进一步在撤血清不同时间点观察Ngb对PI3K/Akt及p38MAPK信号通路的影响，结果显示在撤血清处理9hr的小鼠成神经瘤N2a细胞中过表达Ngb明显上调了Akt及p38的磷酸化水平，同时下调了PTEN的磷酸化水平。双分子荧光互补实验（BiFC）和GSTpull-down结果进一步证实Ngb及其突变体（E53Q,E118Q,K119N,H64A,H64L,Y44D)与EGFR、Akt、p38MAPK和PTEN发生差异性的结合。NgbE53Q这一突变体与野生型Ngb相比同EGFR、Akt和p38MAPK的结合增加，而同PTEN的结合减少，使其对PTEN及Akt的磷酸化水平的调控更为明显，从而增强了Ngb对突起生长的诱导作用。最后我们在小鼠成神经瘤N2a细胞中过表达Ngb后再予无氧无糖(体外模拟缺血)处理，细胞的突起与对照组相比明显增长，证明增加Ngb在缺血病理状态下仍具有促进神经元突起生长的作用。
在脑卒中、老年痴呆、脑/脊髓损伤等疾病中，神经元突起的断损、缩短是脑功能障碍的重要原因，而促进神经元突起的生长或再生是治疗以上脑疾病的关键。因此，Ngb促进神经元突起生长这一新功能为开发治疗神经系统疾病的药物提供了基础。
During the development of the central nervous system (CNS), neurite outgrowth is required for neuronal path findings and the establishment of synaptic connections. Inducing neuritogenesis is a crucial but tough step in treating diseases such as stroke neurodegenerative diseases or traumatic CNS injury. Along with aging, regenerating neurite is of particular difficult because neurons lost their ability to produce neurite after maturation. Understanding clearly the molecular machinery regulating neurite outgrowth is essential for searching effective drug or improving treatments for various neurological diseases.
Neuroglobin (Ngb), a neuronal-or brain-specific respiratory protein, is the third heme-containing globin discovered in mammalians. Most studies have shown that overexpression of neuroglobin exerts neuroprotection against neuronal hypoxia/ischemia-induced damage in cultured neurons and in cerebral ischemic animal models. However, little is known about its role in neuritogenesis.
To investigate the roles and the potential mechanisms of neuroglobin on neurite outgrowth, mouse neuroblstoma N2a cells and primary cultures of cerebral cortical neurons were applied. Respectively, cell culture, molecular biology technology, immunoblotting and cytomorphological methods were performed for this study.
Knocking-down of Ngb exhibited a prominent neurite-deficient phenotype in neuroblstoma N2a cells. Silencing Ngb prevented neurite outgrowth while overexpression of Ngb but not homologous cytoglobin (Cygb) promoted neurite outgrowth upon serum deprivation. In primary cultures of cerebral cortical neurons, Ngb was up-regulated along with culture ages. Overexpression of Ngb but not Cygb promoted neurite outgrowth while knocking-down of Ngb reduced neurite outgrowth in primary cultures of cerebral cortical neurons. Pharmacological studied revealed that Ngb-promoted neurite outgrowth was depended on activities of p38MAPK, Akt but not protein kinase A (PKA), Ca2+/Calmodulin-Dependent Protein Kinase Ⅱ (CaMKII) or the Erk in cortical neurons. Western blots results show that overexpression of Ngb suppressed expression of p-PTEN, enhanced expression of p-AKT and p-p38in N2a cells after withdrawl serum9hr. Bimolecular fluorescence complementation and glutathione S-transferase pull-down assays revealed that neuroglobin and various mutants (E53Q, E118Q, K119N, H64A, H64L, Y44D) bound with EGFR, Akt, p38MAPK and PTEN differentially. Neuroglobin E53Q mutant showed a prominent reduced PTEN-binding but increased Akt-binding, resulting in decreased p-PTEN, increased p-Akt and increased neurite length. Further, overexpression of Ngb promoted neurite outgrowth in N2a during hypoxia. Taken together, our data suggest a physiological and pathological function of Ngb in neuritogenesis in the brain, providing a potential therapeutic target for the axonopathy in neurological diseases.
脑红蛋白（neuroglobin，Ngb）作为一个具有高氧亲和力的组织珠蛋白，在脊椎动物中枢和周围神经系统的神经元中广泛并特异性表达。在过去大量的研究表明Ngb高表达对缺氧/缺血诱导的神经元损伤及脑缺血动物模型具有保护作用。迄今为止，国内外还未见有关Ngb与神经元突起生长相关性的报道。
本研究采用小鼠成神经瘤N2a细胞系和原代皮层神经元作为实验材料和研究对象，利用细胞培养、分子生物学、免疫印迹和细胞形态学等研究技术和方法，进一步探讨了Ngb对神经元突起生长的作用及其潜在的分子机制。
在小鼠成神经瘤N2a细胞中，采用RNA干扰技术抑制Ngb内源性表达后细胞呈现出显著的突起缺陷表型。反之，过表达Ngb后Ngb基因编码的蛋白表达量增加，神经元的突起明显增长。我们进一步在原代培养的大鼠大脑皮层神经元中发现，随神经元发育，突起的增长，Ngb基因表达量显著增加，而脑红蛋白的同源基因细胞红蛋白（cytoglobin,Cygb）的基因表达没有变化。在原代培养的大鼠大脑皮层神经元中过表达Ngb神经元的突起明显增长。反之，抑制原代培养的大鼠大脑皮层神经元中内源性Ngb的表达，神经细胞的突起与对照组相比明显变短。药理学研究发现在原代皮层神经元中Ngb促进突起生长的作用依赖于Akt及p38MAPK蛋白的活性。我们进一步在撤血清不同时间点观察Ngb对PI3K/Akt及p38MAPK信号通路的影响，结果显示在撤血清处理9hr的小鼠成神经瘤N2a细胞中过表达Ngb明显上调了Akt及p38的磷酸化水平，同时下调了PTEN的磷酸化水平。双分子荧光互补实验（BiFC）和GSTpull-down结果进一步证实Ngb及其突变体（E53Q,E118Q,K119N,H64A,H64L,Y44D)与EGFR、Akt、p38MAPK和PTEN发生差异性的结合。NgbE53Q这一突变体与野生型Ngb相比同EGFR、Akt和p38MAPK的结合增加，而同PTEN的结合减少，使其对PTEN及Akt的磷酸化水平的调控更为明显，从而增强了Ngb对突起生长的诱导作用。最后我们在小鼠成神经瘤N2a细胞中过表达Ngb后再予无氧无糖(体外模拟缺血)处理，细胞的突起与对照组相比明显增长，证明增加Ngb在缺血病理状态下仍具有促进神经元突起生长的作用。
在脑卒中、老年痴呆、脑/脊髓损伤等疾病中，神经元突起的断损、缩短是脑功能障碍的重要原因，而促进神经元突起的生长或再生是治疗以上脑疾病的关键。因此，Ngb促进神经元突起生长这一新功能为开发治疗神经系统疾病的药物提供了基础。
During the development of the central nervous system (CNS), neurite outgrowth is required for neuronal path findings and the establishment of synaptic connections. Inducing neuritogenesis is a crucial but tough step in treating diseases such as stroke neurodegenerative diseases or traumatic CNS injury. Along with aging, regenerating neurite is of particular difficult because neurons lost their ability to produce neurite after maturation. Understanding clearly the molecular machinery regulating neurite outgrowth is essential for searching effective drug or improving treatments for various neurological diseases.
Neuroglobin (Ngb), a neuronal-or brain-specific respiratory protein, is the third heme-containing globin discovered in mammalians. Most studies have shown that overexpression of neuroglobin exerts neuroprotection against neuronal hypoxia/ischemia-induced damage in cultured neurons and in cerebral ischemic animal models. However, little is known about its role in neuritogenesis.
To investigate the roles and the potential mechanisms of neuroglobin on neurite outgrowth, mouse neuroblstoma N2a cells and primary cultures of cerebral cortical neurons were applied. Respectively, cell culture, molecular biology technology, immunoblotting and cytomorphological methods were performed for this study.
Knocking-down of Ngb exhibited a prominent neurite-deficient phenotype in neuroblstoma N2a cells. Silencing Ngb prevented neurite outgrowth while overexpression of Ngb but not homologous cytoglobin (Cygb) promoted neurite outgrowth upon serum deprivation. In primary cultures of cerebral cortical neurons, Ngb was up-regulated along with culture ages. Overexpression of Ngb but not Cygb promoted neurite outgrowth while knocking-down of Ngb reduced neurite outgrowth in primary cultures of cerebral cortical neurons. Pharmacological studied revealed that Ngb-promoted neurite outgrowth was depended on activities of p38MAPK, Akt but not protein kinase A (PKA), Ca2+/Calmodulin-Dependent Protein Kinase Ⅱ (CaMKII) or the Erk in cortical neurons. Western blots results show that overexpression of Ngb suppressed expression of p-PTEN, enhanced expression of p-AKT and p-p38in N2a cells after withdrawl serum9hr. Bimolecular fluorescence complementation and glutathione S-transferase pull-down assays revealed that neuroglobin and various mutants (E53Q, E118Q, K119N, H64A, H64L, Y44D) bound with EGFR, Akt, p38MAPK and PTEN differentially. Neuroglobin E53Q mutant showed a prominent reduced PTEN-binding but increased Akt-binding, resulting in decreased p-PTEN, increased p-Akt and increased neurite length. Further, overexpression of Ngb promoted neurite outgrowth in N2a during hypoxia. Taken together, our data suggest a physiological and pathological function of Ngb in neuritogenesis in the brain, providing a potential therapeutic target for the axonopathy in neurological diseases.
引文
[1]Ohnuma, S. and W.A. Harris, Neurogenesis and the cell cycle. Neuron,2003.40(2): p.199-208.
[2]Da, S.J. and C.G. Dotti, Breaking the neuronal sphere:regulation of the actin cytoskeleton in neuritogenesis. Nat Rev Neurosci,2002.3(9):p.694-704.
[3]Diez, D.C.R. and K.G. Storey, Markers in vertebrate neurogenesis. Nat Rev Neurosci,2001.2(11):p.835-9.
[4]Govek, E.E., S.E. Newey and L. Van Aelst, The role of the Rho GTPases in neuronal development. Genes Dev,2005.19(1):p.1-49.
[5]Barnes, A.P. and F. Polleux, Establishment of axon-dendrite polarity in developing neurons. Annu Rev Neurosci,2009.32:p.347-81.
[6]Yoshikawa, S. and J.B. Thomas, Secreted cell signaling molecules in axon guidance. Curr Opin Neurobiol,2004.14(1):p.45-50.
[7]Huang, E.J. and L.F. Reichardt, Neurotrophins:roles in neuronal development and function. Annu Rev Neurosci,2001.24:p.677-736.
[8]Rodriguez, O.C., et al., Conserved microtubule-actin interactions in cell movement and morphogenesis. Nat Cell Biol,2003.5(7):p.599-609.
[9]Huber, A.B., et al., Signaling at the growth cone:ligand-receptor complexes and the control of axon growth and guidance. Annu Rev Neurosci,2003.26:p.509-63.
[10]Meberg, P.J. and J.R. Bamburg, Increase in neurite outgrowth mediated by overexpression of actin depolymerizing factor. J Neurosci,2000.20(7):p.2459-69.
[11]Boukhelifa, M., et al., A role for the cytoskeleton-associated protein palladin in neurite outgrowth. Mol Biol Cell,2001.12(9):p.2721-9.
[12]Vaudry, D., et al., Signaling pathways for PC12cell differentiation:making the right connections. Science,2002.296(5573):p.1648-9.
[13]Zhou, F.Q. and W.D. Snider, Intracellular control of developmental and regenerative axon growth. Philos Trans R Soc Lond B Biol Sci,2006.361(1473):p.1575-92.
[14]Hafner, A., N. Obermajer and J. Kos, gamma-Enolase C-terminal peptide promotes cell survival and neurite outgrowth by activation of the PI3K/Akt and MAPK/ERK signalling pathways. Biochem J,2012.443(2):p.439-50.
[15]Conrad, S., et al., Neogenin-RGMa signaling at the growth cone is bone morphogenetic protein-independent and involves RhoA, ROCK, and PKC. J Biol Chem,2007.282(22):p.16423-33.
[16]Bodrikov, V., et al., NCAM induces CaMKIIalpha-mediated RPTPalpha phosphorylation to enhance its catalytic activity and neurite outgrowth. J Cell Biol,2008.182(6):p.1185-200.
[17]Takeda, K. and H. Ichijo, Neuronal p38MAPK signalling:an emerging regulator of cell fate and function in the nervous system. Genes Cells,2002.7(11):p.1099-111.
[18]Alabed, Y.Z., et al., GSK3beta regulates myelin-dependent axon outgrowth inhibition through CRMP4. J Neurosci,2010.30(16):p.5635-43.
[19]Tanaka, S., et al., Neural expression of G protein-coupled receptors GPR3, GPR6, and GPR12up-regulates cyclic AMP levels and promotes neurite outgrowth. J Biol Chem,2007.282(14):p.10506-15.
[20]Wystub, S., et al., Localization of neuroglobin protein in the mouse brain. Neurosci Lett,2003.346(1-2):p.114-6.
[21]Branda, M. and J.R. Wands, Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma. Hepatology,2006.43(5):p.891-902.
[22]Schmidt, M., et al., How does the eye breathe? Evidence for neuroglobin-mediated oxygen supply in the mammalian retina. J Biol Chem,2003.278(3):p.1932-5.
[23]Hundahl, C, et al., Effects of short-term hypoxia on neuroglobin levels and localization in mouse brain tissues. Neuropathol Appl Neurobiol,2005.31(6):p.610-7.
[24]Wang, X., et al., Effects of neuroglobin overexpression on acute brain injury and long-term outcomes after focal cerebral ischemia. Stroke,2008.39(6):p.1869-74.
[25]Yu, Z., et al., Neuroprotective roles and mechanisms of neuroglobin. Neurol Res,2009.31(2):p.122-7.
[26]Wakasugi, K., T. Nakano and I. Morishima, Oxidized human neuroglobin acts as a heterotrimeric Galpha protein guanine nucleotide dissociation inhibitor. J Biol Chem,2003.278(38):p.36505-12.
[27]El-Assal, O.N., et al., Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver:possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology,1998.27(6):p.1554-62.
[28]Poon, R.T., et al., High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma:a prospective study. Oncol Rep,2004.11(5):p.1077-84.
[29]Antao, S.T., et al., Neuroglobin overexpression in cultured human neuronal cells protects against hydrogen peroxide insult via activating phosphoinositide-3kinase and opening the mitochondrial K(ATP) channel. Antioxid Redox Signal,2010.13(6):p.769-81.
[30]Cui, H., et al., Heparanase enhances nerve-growth-factor-induced PC12cell neuritogenesis via the p38MAPK pathway. Biochem J,2011.440(2):p.273-82.
[31]Alabed, Y.Z., et al., GSK3beta regulates myelin-dependent axon outgrowth inhibition through CRMP4. J Neurosci,2010.30(16):p.5635-43.
[32]Zach, S., S. Felk and F. Gillardon, Signal transduction protein array analysis links LRRK2to Ste20kinases and PKC zeta that modulate neuronal plasticity. PLoS One,2010.5(10):p. e13191.
[33]Borodinsky, L.N., et al., GABA-induced neurite outgrowth of cerebellar granule cells is mediated by GABA(A) receptor activation, calcium influx and CaMKII and erkl/2pathways. J Neurochem,2003.84(6):p.1411-20.
[34]Lai, H.C., et al.,Neurotrophic effect of citrus5-hydroxy-3,6,7,8,3',4'-hexamethoxy-flavone:promotion of neurite outgrowth via cAMP/PKA/CREB pathway in PC12cells. PLoS One,2011.6(11):p. e28280.
[35]Yu, Z., et al., Neuroglobin-overexpression alters hypoxic response gene expression in primary neuron culture following oxygen glucose deprivation. Neuroscience,2009.162(2):p.396-403.
[36]Milas, L., et al., Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys,2004.58(3):p.966-71.
[37]Trent, J.R., R.A. Watts and M.S. Hargrove, Human neuroglobin, a hexacoordinate hemoglobin that reversibly binds oxygen. J Biol Chem,2001.276(32):p.30106-10.
[38]Wakasugi, K. and I. Morishima, Identification of residues in human neuroglobin crucial for Guanine nucleotide dissociation inhibitor activity. Biochemistry,2005.44(8):p.2943-8.
[39]Brunori, M. and B. Vallone, A globin for the brain. FASEB J,2006.20(13):p.2192-7.
[40]Jayaraman, T., et al.,14-3-3binding and phosphorylation of neuroglobin during hypoxia modulate six-to-five heme pocket coordination and rate of nitrite reduction to nitric oxide. J Biol Chem,2011.286(49):p.42679-89.
[41]Zorina, Y., R. Iyengar and K.D. Bromberg, Cannabinoid1receptor and interleukin-6receptor together induce integration of protein kinase and transcription factor signaling to trigger neurite outgrowth. J Biol Chem,2010.285(2):p.1358-70.
[42]Vaudry, D., et al., Signaling pathways for PC12cell differentiation:making the right connections. Science,2002.296(5573):p.1648-9.
[43]Read, D.E. and A.M. Gorman, Involvement of Akt in neurite outgrowth. Cell Mol Life Sci,2009.66(18):p.2975-84.
[44]Antao, S.T., et al., Neuroglobin overexpression in cultured human neuronal cells protects against hydrogen peroxide insult via activating phosphoinositide-3kinase and opening the mitochondrial K(ATP) channel. Antioxid Redox Signal,2010.13(6):p.769-81.
[45]Chen, L.M., et al., Neuroglobin attenuates Alzheimer-like tau hyperphosphorylation by activating Akt signaling. J Neurochem,2012.120(1):p.157-64.
[46]Christie, K.J., et al., PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. J Neurosci,2010.30(27):p.9306-15.
[47]Giuffre, A., et al., Neuroglobin:enzymatic reduction and oxygen affinity. Biochem Biophys Res Commun,2008.367(4):p.893-8.
[1]Whiteman, E.L., H. Cho and M.J. Birnbaum, Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab,2002.13(10):p.444-51.
[2]Park, D., et al., An essential role for Aktl in dendritic cell function and tumor immunotherapy. Nat Biotechnol,2006.24(12):p.1581-90.
[3]Rychahou, P.G., et al., Akt2overexpression plays a critical role in the establishment of colorectal cancer metastasis. Proc Natl Acad Sci U S A,2008.105(51):p.20315-20.
[4]Easton, R.M., et al., Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol,2005.25(5):p.1869-78.
[5]Anderson, K.E., et al., Translocation of PDK-1to the plasma membrane is important in allowing PDK-1to activate protein kinase B. Curr Biol,1998.8(12):p.684-91.
[6]Alessi, D.R., et al., Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J,1996.15(23):p.6541-51.
[7]Brunet, A., et al., Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell,1999.96(6):p.857-68.
[8]Ahn, K.S. and B.B. Aggarwal, Transcription factor NF-kappaB:a sensor for smoke and stress signals. Ann N Y Acad Sci,2005.1056:p.218-33.
[9]Romashkova, J.A. and S.S. Makarov, NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature,1999.401(6748):p.86-90.
[10]Zhou, B.P., et al., HER-2/neu induces p53ubiquitination via Akt-mediated MDM2phosphorylation. Nat Cell Biol,2001.3(11):p.973-82.
[11]Qi, X.J., G.M. Wildey and P.H. Howe, Evidence that Ser87of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem,2006.281(2):p.813-23.
[12]Datta, S.R., et al., Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell,1997.91(2):p.231-41.
[13]Huang, E.J. and L.F. Reichardt, Trk receptors:roles in neuronal signal transduction. Annu Rev Biochem,2003.72:p.609-42.
[14]Cross, D.A., et al., Inhibition of glycogen synthase kinase-3by insulin mediated by protein kinase B. Nature,1995.378(6559):p.785-9.
[15]Salas, T.R., et al., Alleviating the suppression of glycogen synthase kinase-3beta by Akt leads to the phosphorylation of cAMP-response element-binding protein and its transactivation in intact cell nuclei. J Biol Chem,2003.278(42):p.41338-46.
[16]Nave, B.T., et al., Mammalian target of rapamycin is a direct target for protein kinase B:identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J,1999.344Pt2:p.427-31.
[17]Asnaghi, L., et al., Bcl-2phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene,2004.23(34):p.5781-91.
[18]Li, X.Y., et al., CREB is a regulatory target for the protein kinase Akt/PKB in the differentiation of pancreatic ductal cells into islet beta-cells mediated by hepatocyte growth factor. Biochem Biophys Res Commun,2011.404(2):p.711-6.
[19]Konishi, H., et al., Identification of peripherin as a Akt substrate in neurons. J Biol Chem,2007.282(32):p.23491-9.
[20]Kim, H., et al., Delta-catenin-induced dendritic morphogenesis. An essential role of p190RhoGEF interaction through Aktl-mediated phosphorylation. J Biol Chem,2008.283(2):p.977-87.
[21]Znamensky, V., et al., Estrogen levels regulate the subcellular distribution of phosphorylated Akt in hippocampal CA1dendrites. J Neurosci,2003.23(6):p.2340-7.
[22]Akama, K.T. and B.S. McEwen, Estrogen stimulates postsynaptic density-95rapid protein synthesis via the Akt/protein kinase B pathway. J Neurosci,2003.23(6):p.2333-9.
[23]Wang, Q., et al., Control of synaptic strength, a novel function of Akt. Neuron, 2003.38(6):p.915-28.
[24]Huang, E.J. and L.F. Reichardt, Trk receptors:roles in neuronal signal transduction. Annu Rev Biochem,2003.72:p.609-42.
[25]Kimpinski, K. and K. Mearow, Neurite growth promotion by nerve growth factor and insulin-like growth factor-1in cultured adult sensory neurons:role of phosphoinositide3-kinase and mitogen activated protein kinase. J Neurosci Res,2001.63(6):p.486-99.
[26]Jones, D.M., et al., The synergistic effects of NGF and IGF-1on neurite growth in adult sensory neurons:convergence on the PI3-kinase signaling pathway. J Neurochem,2003.86(5):p.1116-28.
[27]Kao, H.T., et al., A protein kinase A-dependent molecular switch in synapsins regulates neurite outgrowth. Nat Neurosci,2002.5(5):p.431-7.
[28]Kamata, Y., et al., Induction of neurite outgrowth in PC12cells by the medium-chain fatty acid octanoic acid. Neuroscience,2007.146(3):p.1073-81.
[29]Zheng, J., et al., Clathrin-dependent endocytosis is required for TrkB-dependent Akt-mediated neuronal protection and dendritic growth. J Biol Chem,2008.283(19):p.13280-8.
[30]Lim, C.S. and R.S. Walikonis, Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway. Cell Signal,2008.20(5):p.825-35.
[31]Tucker, B.A., M. Rahimtula and K.M. Mearow, Src and FAK are key early signalling intermediates required for neurite growth in NGF-responsive adult DRG neurons. Cell Signal,2008.20(1):p.241-57.
[32]Tucker, B.A., M. Rahimtula and K.M. Mearow, Laminin and growth factor receptor activation stimulates differential growth responses in subpopulations of adult DRG neurons. Eur J Neurosci,2006.24(3):p.676-90.
[33]Read, D.E., H.K. Reed and A.M. Gorman, Heat shock enhances NGF-induced neurite elongation which is not mediated by Hsp25in PC12cells. Brain Res,2008. 1221:p.14-23.
[34]Higuchi, M., et al., The phosphatidylinositol-3kinase (PI3K)-Akt pathway suppresses neurite branch formation in NGF-treated PC12cells. Genes Cells,2003.8(8):p.657-69.
[35]Kim, Y., et al., A positive role of the PI3-K/Akt signaling pathway in PC12cell differentiation. Mol Cells,2004.18(3):p.353-9.
[36]Namikawa, K., et al., Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. J Neurosci,2000.20(8):p.2875-86.
[37]Kim, Y, et al., A positive role of the PI3-K/Akt signaling pathway in PC12cell differentiation. Mol Cells,2004.18(3):p.353-9.
[38]Ashcroft, M., et al., The selective and inducible activation of endogenous PI3-kinase in PC12cells results in efficient NGF-mediated survival but defective neurite outgrowth. Oncogene,1999.18(32):p.4586-97.
[39]Kamata, Y., et al., Induction of neurite outgrowth in PC12cells by the medium-chain fatty acid octanoic acid. Neuroscience,2007.146(3):p.1073-81.
[40]Kuruvilla, R., H. Ye and D.D. Ginty, Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron,2000.27(3):p.499-512.
[41]Jackson, T.R., et al., Initiation and maintenance of NGF-stimulated neurite outgrowth requires activation of a phosphoinositide3-kinase. J Cell Sci,1996.109(Pt2):p.289-300.
[42]Markus, A., J. Zhong and W.D. Snider, Raf and akt mediate distinct aspects of sensory axon growth. Neuron,2002.35(1):p.65-76.
[43]Jaworski, J., et al., Control of dendritic arborization by the phosphoinositide-3'-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci,2005.25(49):p.11300-12.
[44]Kumar, V., et al., Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci,2005.25(49):p.11288-99.
[45]Yoshimura, T., et al.,Ras regulates neuronal polarity via the PI3-kinase/Akt/GSK-3beta/CRMP-2pathway. Biochem Biophys Res Commun,2006.340(1):p.62-8.
[46]Lawlor, M.A. and D.R. Alessi, PKB/Akt:a key mediator of cell proliferation, survival and insulin responses? J Cell Sci,2001.114(Pt16):p.2903-10.
[47]Gartner, A., X. Huang and A. Hall, Neuronal polarity is regulated by glycogen synthase kinase-3(GSK-3beta) independently of Akt/PKB serine phosphorylation. J Cell Sci,2006.119(Pt19):p.3927-34.
[48]Zhou, F.Q., et al., NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC. Neuron,2004.42(6):p.897-912.
[49]Jiang, H, et al., Both the establishment and the maintenance of neuronal polarity require active mechanisms:critical roles of GSK-3beta and its upstream regulators. Cell,2005.120(1):p.123-35.
[50]Suzuki, Y., et al., Collapsin response mediator protein-2accelerates axon regeneration of nerve-injured motor neurons of rat. J Neurochem,2003.86(4):p.1042-50.
[51]Yoshimura, T., N. Arimura and K. Kaibuchi, Signaling networks in neuronal polarization. J Neurosci,2006.26(42):p.10626-30.
[52]Enomoto, A., et al., Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell,2005.9(3):p.389-402.
[53]Kwon, T., et al., Akt protein kinase inhibits Racl-GTP binding through phosphorylation at serine71of Racl. J Biol Chem,2000.275(1):p.423-8.
[54]Konishi, H, et al., Identification of peripherin as a Akt substrate in neurons. J Biol Chem,2007.282(32):p.23491-9.
[55]Verma, P., et al., Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. J Neurosci,2005.25(2):p.331-42.
[56]Du K and M. Montminy, CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem,1998.273(49):p.32377-9.
[57]Shimomura, A., et al., Dominant negative ATF1blocks cyclic AMP-induced neurite outgrowth in PC12D cells. J Neurochem,1998.70(3):p.1029-34.
[58]Jessen, U., et al., The transcription factors CREB and c-Fos play key roles in NCAM-mediated neuritogenesis in PC12-E2cells. J Neurochem,2001.79(6):p.1149-60.
[59]Gutierrez, H., et al., NF-kappaB signalling regulates the growth of neural processes in the developing PNS and CNS. Development,2005.132(7):p.1713-26.
[60]Ozes, O.N., et al., NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature,1999.401(6748):p.82-5.
[61]Daniels, R.H., P.S. Hall and G.M. Bokoch, Membrane targeting of p21-activated kinase1(PAK1) induces neurite outgrowth from PC12cells. EMBO J,1998.17(3): p.754-64.
[62]Jossin, Y. and A.M. Goffinet, Reelin signals through phosphatidylinositol3-kinase and Akt to control cortical development and through mTor to regulate dendritic growth. Mol Cell Biol,2007.27(20):p.7113-24.
[63]Jones, S.B., et al., Glutamate-induced delta-catenin redistribution and dissociation from postsynaptic receptor complexes. Neuroscience,2002.115(4):p.1009-21.
[64]Kim, K., et al., Dendrite-like process formation and cytoskeletal remodeling regulated by delta-catenin expression. Exp Cell Res,2002.275(2):p.171-84.
[2]Da, S.J. and C.G. Dotti, Breaking the neuronal sphere:regulation of the actin cytoskeleton in neuritogenesis. Nat Rev Neurosci,2002.3(9):p.694-704.
[3]Diez, D.C.R. and K.G. Storey, Markers in vertebrate neurogenesis. Nat Rev Neurosci,2001.2(11):p.835-9.
[4]Govek, E.E., S.E. Newey and L. Van Aelst, The role of the Rho GTPases in neuronal development. Genes Dev,2005.19(1):p.1-49.
[5]Barnes, A.P. and F. Polleux, Establishment of axon-dendrite polarity in developing neurons. Annu Rev Neurosci,2009.32:p.347-81.
[6]Yoshikawa, S. and J.B. Thomas, Secreted cell signaling molecules in axon guidance. Curr Opin Neurobiol,2004.14(1):p.45-50.
[7]Huang, E.J. and L.F. Reichardt, Neurotrophins:roles in neuronal development and function. Annu Rev Neurosci,2001.24:p.677-736.
[8]Rodriguez, O.C., et al., Conserved microtubule-actin interactions in cell movement and morphogenesis. Nat Cell Biol,2003.5(7):p.599-609.
[9]Huber, A.B., et al., Signaling at the growth cone:ligand-receptor complexes and the control of axon growth and guidance. Annu Rev Neurosci,2003.26:p.509-63.
[10]Meberg, P.J. and J.R. Bamburg, Increase in neurite outgrowth mediated by overexpression of actin depolymerizing factor. J Neurosci,2000.20(7):p.2459-69.
[11]Boukhelifa, M., et al., A role for the cytoskeleton-associated protein palladin in neurite outgrowth. Mol Biol Cell,2001.12(9):p.2721-9.
[12]Vaudry, D., et al., Signaling pathways for PC12cell differentiation:making the right connections. Science,2002.296(5573):p.1648-9.
[13]Zhou, F.Q. and W.D. Snider, Intracellular control of developmental and regenerative axon growth. Philos Trans R Soc Lond B Biol Sci,2006.361(1473):p.1575-92.
[14]Hafner, A., N. Obermajer and J. Kos, gamma-Enolase C-terminal peptide promotes cell survival and neurite outgrowth by activation of the PI3K/Akt and MAPK/ERK signalling pathways. Biochem J,2012.443(2):p.439-50.
[15]Conrad, S., et al., Neogenin-RGMa signaling at the growth cone is bone morphogenetic protein-independent and involves RhoA, ROCK, and PKC. J Biol Chem,2007.282(22):p.16423-33.
[16]Bodrikov, V., et al., NCAM induces CaMKIIalpha-mediated RPTPalpha phosphorylation to enhance its catalytic activity and neurite outgrowth. J Cell Biol,2008.182(6):p.1185-200.
[17]Takeda, K. and H. Ichijo, Neuronal p38MAPK signalling:an emerging regulator of cell fate and function in the nervous system. Genes Cells,2002.7(11):p.1099-111.
[18]Alabed, Y.Z., et al., GSK3beta regulates myelin-dependent axon outgrowth inhibition through CRMP4. J Neurosci,2010.30(16):p.5635-43.
[19]Tanaka, S., et al., Neural expression of G protein-coupled receptors GPR3, GPR6, and GPR12up-regulates cyclic AMP levels and promotes neurite outgrowth. J Biol Chem,2007.282(14):p.10506-15.
[20]Wystub, S., et al., Localization of neuroglobin protein in the mouse brain. Neurosci Lett,2003.346(1-2):p.114-6.
[21]Branda, M. and J.R. Wands, Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma. Hepatology,2006.43(5):p.891-902.
[22]Schmidt, M., et al., How does the eye breathe? Evidence for neuroglobin-mediated oxygen supply in the mammalian retina. J Biol Chem,2003.278(3):p.1932-5.
[23]Hundahl, C, et al., Effects of short-term hypoxia on neuroglobin levels and localization in mouse brain tissues. Neuropathol Appl Neurobiol,2005.31(6):p.610-7.
[24]Wang, X., et al., Effects of neuroglobin overexpression on acute brain injury and long-term outcomes after focal cerebral ischemia. Stroke,2008.39(6):p.1869-74.
[25]Yu, Z., et al., Neuroprotective roles and mechanisms of neuroglobin. Neurol Res,2009.31(2):p.122-7.
[26]Wakasugi, K., T. Nakano and I. Morishima, Oxidized human neuroglobin acts as a heterotrimeric Galpha protein guanine nucleotide dissociation inhibitor. J Biol Chem,2003.278(38):p.36505-12.
[27]El-Assal, O.N., et al., Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver:possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology,1998.27(6):p.1554-62.
[28]Poon, R.T., et al., High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma:a prospective study. Oncol Rep,2004.11(5):p.1077-84.
[29]Antao, S.T., et al., Neuroglobin overexpression in cultured human neuronal cells protects against hydrogen peroxide insult via activating phosphoinositide-3kinase and opening the mitochondrial K(ATP) channel. Antioxid Redox Signal,2010.13(6):p.769-81.
[30]Cui, H., et al., Heparanase enhances nerve-growth-factor-induced PC12cell neuritogenesis via the p38MAPK pathway. Biochem J,2011.440(2):p.273-82.
[31]Alabed, Y.Z., et al., GSK3beta regulates myelin-dependent axon outgrowth inhibition through CRMP4. J Neurosci,2010.30(16):p.5635-43.
[32]Zach, S., S. Felk and F. Gillardon, Signal transduction protein array analysis links LRRK2to Ste20kinases and PKC zeta that modulate neuronal plasticity. PLoS One,2010.5(10):p. e13191.
[33]Borodinsky, L.N., et al., GABA-induced neurite outgrowth of cerebellar granule cells is mediated by GABA(A) receptor activation, calcium influx and CaMKII and erkl/2pathways. J Neurochem,2003.84(6):p.1411-20.
[34]Lai, H.C., et al.,Neurotrophic effect of citrus5-hydroxy-3,6,7,8,3',4'-hexamethoxy-flavone:promotion of neurite outgrowth via cAMP/PKA/CREB pathway in PC12cells. PLoS One,2011.6(11):p. e28280.
[35]Yu, Z., et al., Neuroglobin-overexpression alters hypoxic response gene expression in primary neuron culture following oxygen glucose deprivation. Neuroscience,2009.162(2):p.396-403.
[36]Milas, L., et al., Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys,2004.58(3):p.966-71.
[37]Trent, J.R., R.A. Watts and M.S. Hargrove, Human neuroglobin, a hexacoordinate hemoglobin that reversibly binds oxygen. J Biol Chem,2001.276(32):p.30106-10.
[38]Wakasugi, K. and I. Morishima, Identification of residues in human neuroglobin crucial for Guanine nucleotide dissociation inhibitor activity. Biochemistry,2005.44(8):p.2943-8.
[39]Brunori, M. and B. Vallone, A globin for the brain. FASEB J,2006.20(13):p.2192-7.
[40]Jayaraman, T., et al.,14-3-3binding and phosphorylation of neuroglobin during hypoxia modulate six-to-five heme pocket coordination and rate of nitrite reduction to nitric oxide. J Biol Chem,2011.286(49):p.42679-89.
[41]Zorina, Y., R. Iyengar and K.D. Bromberg, Cannabinoid1receptor and interleukin-6receptor together induce integration of protein kinase and transcription factor signaling to trigger neurite outgrowth. J Biol Chem,2010.285(2):p.1358-70.
[42]Vaudry, D., et al., Signaling pathways for PC12cell differentiation:making the right connections. Science,2002.296(5573):p.1648-9.
[43]Read, D.E. and A.M. Gorman, Involvement of Akt in neurite outgrowth. Cell Mol Life Sci,2009.66(18):p.2975-84.
[44]Antao, S.T., et al., Neuroglobin overexpression in cultured human neuronal cells protects against hydrogen peroxide insult via activating phosphoinositide-3kinase and opening the mitochondrial K(ATP) channel. Antioxid Redox Signal,2010.13(6):p.769-81.
[45]Chen, L.M., et al., Neuroglobin attenuates Alzheimer-like tau hyperphosphorylation by activating Akt signaling. J Neurochem,2012.120(1):p.157-64.
[46]Christie, K.J., et al., PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. J Neurosci,2010.30(27):p.9306-15.
[47]Giuffre, A., et al., Neuroglobin:enzymatic reduction and oxygen affinity. Biochem Biophys Res Commun,2008.367(4):p.893-8.
[1]Whiteman, E.L., H. Cho and M.J. Birnbaum, Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab,2002.13(10):p.444-51.
[2]Park, D., et al., An essential role for Aktl in dendritic cell function and tumor immunotherapy. Nat Biotechnol,2006.24(12):p.1581-90.
[3]Rychahou, P.G., et al., Akt2overexpression plays a critical role in the establishment of colorectal cancer metastasis. Proc Natl Acad Sci U S A,2008.105(51):p.20315-20.
[4]Easton, R.M., et al., Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol,2005.25(5):p.1869-78.
[5]Anderson, K.E., et al., Translocation of PDK-1to the plasma membrane is important in allowing PDK-1to activate protein kinase B. Curr Biol,1998.8(12):p.684-91.
[6]Alessi, D.R., et al., Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J,1996.15(23):p.6541-51.
[7]Brunet, A., et al., Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell,1999.96(6):p.857-68.
[8]Ahn, K.S. and B.B. Aggarwal, Transcription factor NF-kappaB:a sensor for smoke and stress signals. Ann N Y Acad Sci,2005.1056:p.218-33.
[9]Romashkova, J.A. and S.S. Makarov, NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature,1999.401(6748):p.86-90.
[10]Zhou, B.P., et al., HER-2/neu induces p53ubiquitination via Akt-mediated MDM2phosphorylation. Nat Cell Biol,2001.3(11):p.973-82.
[11]Qi, X.J., G.M. Wildey and P.H. Howe, Evidence that Ser87of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem,2006.281(2):p.813-23.
[12]Datta, S.R., et al., Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell,1997.91(2):p.231-41.
[13]Huang, E.J. and L.F. Reichardt, Trk receptors:roles in neuronal signal transduction. Annu Rev Biochem,2003.72:p.609-42.
[14]Cross, D.A., et al., Inhibition of glycogen synthase kinase-3by insulin mediated by protein kinase B. Nature,1995.378(6559):p.785-9.
[15]Salas, T.R., et al., Alleviating the suppression of glycogen synthase kinase-3beta by Akt leads to the phosphorylation of cAMP-response element-binding protein and its transactivation in intact cell nuclei. J Biol Chem,2003.278(42):p.41338-46.
[16]Nave, B.T., et al., Mammalian target of rapamycin is a direct target for protein kinase B:identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J,1999.344Pt2:p.427-31.
[17]Asnaghi, L., et al., Bcl-2phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene,2004.23(34):p.5781-91.
[18]Li, X.Y., et al., CREB is a regulatory target for the protein kinase Akt/PKB in the differentiation of pancreatic ductal cells into islet beta-cells mediated by hepatocyte growth factor. Biochem Biophys Res Commun,2011.404(2):p.711-6.
[19]Konishi, H., et al., Identification of peripherin as a Akt substrate in neurons. J Biol Chem,2007.282(32):p.23491-9.
[20]Kim, H., et al., Delta-catenin-induced dendritic morphogenesis. An essential role of p190RhoGEF interaction through Aktl-mediated phosphorylation. J Biol Chem,2008.283(2):p.977-87.
[21]Znamensky, V., et al., Estrogen levels regulate the subcellular distribution of phosphorylated Akt in hippocampal CA1dendrites. J Neurosci,2003.23(6):p.2340-7.
[22]Akama, K.T. and B.S. McEwen, Estrogen stimulates postsynaptic density-95rapid protein synthesis via the Akt/protein kinase B pathway. J Neurosci,2003.23(6):p.2333-9.
[23]Wang, Q., et al., Control of synaptic strength, a novel function of Akt. Neuron, 2003.38(6):p.915-28.
[24]Huang, E.J. and L.F. Reichardt, Trk receptors:roles in neuronal signal transduction. Annu Rev Biochem,2003.72:p.609-42.
[25]Kimpinski, K. and K. Mearow, Neurite growth promotion by nerve growth factor and insulin-like growth factor-1in cultured adult sensory neurons:role of phosphoinositide3-kinase and mitogen activated protein kinase. J Neurosci Res,2001.63(6):p.486-99.
[26]Jones, D.M., et al., The synergistic effects of NGF and IGF-1on neurite growth in adult sensory neurons:convergence on the PI3-kinase signaling pathway. J Neurochem,2003.86(5):p.1116-28.
[27]Kao, H.T., et al., A protein kinase A-dependent molecular switch in synapsins regulates neurite outgrowth. Nat Neurosci,2002.5(5):p.431-7.
[28]Kamata, Y., et al., Induction of neurite outgrowth in PC12cells by the medium-chain fatty acid octanoic acid. Neuroscience,2007.146(3):p.1073-81.
[29]Zheng, J., et al., Clathrin-dependent endocytosis is required for TrkB-dependent Akt-mediated neuronal protection and dendritic growth. J Biol Chem,2008.283(19):p.13280-8.
[30]Lim, C.S. and R.S. Walikonis, Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway. Cell Signal,2008.20(5):p.825-35.
[31]Tucker, B.A., M. Rahimtula and K.M. Mearow, Src and FAK are key early signalling intermediates required for neurite growth in NGF-responsive adult DRG neurons. Cell Signal,2008.20(1):p.241-57.
[32]Tucker, B.A., M. Rahimtula and K.M. Mearow, Laminin and growth factor receptor activation stimulates differential growth responses in subpopulations of adult DRG neurons. Eur J Neurosci,2006.24(3):p.676-90.
[33]Read, D.E., H.K. Reed and A.M. Gorman, Heat shock enhances NGF-induced neurite elongation which is not mediated by Hsp25in PC12cells. Brain Res,2008. 1221:p.14-23.
[34]Higuchi, M., et al., The phosphatidylinositol-3kinase (PI3K)-Akt pathway suppresses neurite branch formation in NGF-treated PC12cells. Genes Cells,2003.8(8):p.657-69.
[35]Kim, Y., et al., A positive role of the PI3-K/Akt signaling pathway in PC12cell differentiation. Mol Cells,2004.18(3):p.353-9.
[36]Namikawa, K., et al., Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. J Neurosci,2000.20(8):p.2875-86.
[37]Kim, Y, et al., A positive role of the PI3-K/Akt signaling pathway in PC12cell differentiation. Mol Cells,2004.18(3):p.353-9.
[38]Ashcroft, M., et al., The selective and inducible activation of endogenous PI3-kinase in PC12cells results in efficient NGF-mediated survival but defective neurite outgrowth. Oncogene,1999.18(32):p.4586-97.
[39]Kamata, Y., et al., Induction of neurite outgrowth in PC12cells by the medium-chain fatty acid octanoic acid. Neuroscience,2007.146(3):p.1073-81.
[40]Kuruvilla, R., H. Ye and D.D. Ginty, Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron,2000.27(3):p.499-512.
[41]Jackson, T.R., et al., Initiation and maintenance of NGF-stimulated neurite outgrowth requires activation of a phosphoinositide3-kinase. J Cell Sci,1996.109(Pt2):p.289-300.
[42]Markus, A., J. Zhong and W.D. Snider, Raf and akt mediate distinct aspects of sensory axon growth. Neuron,2002.35(1):p.65-76.
[43]Jaworski, J., et al., Control of dendritic arborization by the phosphoinositide-3'-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci,2005.25(49):p.11300-12.
[44]Kumar, V., et al., Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci,2005.25(49):p.11288-99.
[45]Yoshimura, T., et al.,Ras regulates neuronal polarity via the PI3-kinase/Akt/GSK-3beta/CRMP-2pathway. Biochem Biophys Res Commun,2006.340(1):p.62-8.
[46]Lawlor, M.A. and D.R. Alessi, PKB/Akt:a key mediator of cell proliferation, survival and insulin responses? J Cell Sci,2001.114(Pt16):p.2903-10.
[47]Gartner, A., X. Huang and A. Hall, Neuronal polarity is regulated by glycogen synthase kinase-3(GSK-3beta) independently of Akt/PKB serine phosphorylation. J Cell Sci,2006.119(Pt19):p.3927-34.
[48]Zhou, F.Q., et al., NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC. Neuron,2004.42(6):p.897-912.
[49]Jiang, H, et al., Both the establishment and the maintenance of neuronal polarity require active mechanisms:critical roles of GSK-3beta and its upstream regulators. Cell,2005.120(1):p.123-35.
[50]Suzuki, Y., et al., Collapsin response mediator protein-2accelerates axon regeneration of nerve-injured motor neurons of rat. J Neurochem,2003.86(4):p.1042-50.
[51]Yoshimura, T., N. Arimura and K. Kaibuchi, Signaling networks in neuronal polarization. J Neurosci,2006.26(42):p.10626-30.
[52]Enomoto, A., et al., Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell,2005.9(3):p.389-402.
[53]Kwon, T., et al., Akt protein kinase inhibits Racl-GTP binding through phosphorylation at serine71of Racl. J Biol Chem,2000.275(1):p.423-8.
[54]Konishi, H, et al., Identification of peripherin as a Akt substrate in neurons. J Biol Chem,2007.282(32):p.23491-9.
[55]Verma, P., et al., Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. J Neurosci,2005.25(2):p.331-42.
[56]Du K and M. Montminy, CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem,1998.273(49):p.32377-9.
[57]Shimomura, A., et al., Dominant negative ATF1blocks cyclic AMP-induced neurite outgrowth in PC12D cells. J Neurochem,1998.70(3):p.1029-34.
[58]Jessen, U., et al., The transcription factors CREB and c-Fos play key roles in NCAM-mediated neuritogenesis in PC12-E2cells. J Neurochem,2001.79(6):p.1149-60.
[59]Gutierrez, H., et al., NF-kappaB signalling regulates the growth of neural processes in the developing PNS and CNS. Development,2005.132(7):p.1713-26.
[60]Ozes, O.N., et al., NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature,1999.401(6748):p.82-5.
[61]Daniels, R.H., P.S. Hall and G.M. Bokoch, Membrane targeting of p21-activated kinase1(PAK1) induces neurite outgrowth from PC12cells. EMBO J,1998.17(3): p.754-64.
[62]Jossin, Y. and A.M. Goffinet, Reelin signals through phosphatidylinositol3-kinase and Akt to control cortical development and through mTor to regulate dendritic growth. Mol Cell Biol,2007.27(20):p.7113-24.
[63]Jones, S.B., et al., Glutamate-induced delta-catenin redistribution and dissociation from postsynaptic receptor complexes. Neuroscience,2002.115(4):p.1009-21.
[64]Kim, K., et al., Dendrite-like process formation and cytoskeletal remodeling regulated by delta-catenin expression. Exp Cell Res,2002.275(2):p.171-84.