臺灣博碩士論文加值系統

磷酸化蛋白 Collapsin response mediator protein-2 (CRMP-2) 具備調節神經軸突生長以及調控微小管動態活動 (microtubule dynamics) 的功能。過去的研究發現在愛滋海默症 (Alzheimer's disease) 病變的腦組織中，CRMP-2 呈現異常的高度磷酸化狀態，而且愛滋海默症的病程發展 (pathogenesis) 與磷酸化激酶 glycogen synthase kinase-3 (GSK-3) 的活性變化有關。一般認為 CRMP-2 只存在於神經組織中，然而實際上有關 CRMP-2 於非神經細胞中的表現情形仍未有清楚結論。本論文中，我運用西方墨點法 (Western blotting) 以及反轉錄酶-聚合酶連鎖反應法 (RT-PCR) 證明 CRMP-2 不僅存在於神經細胞中，亦表現於非神經細胞之中。CRMP-2 於不同的細胞株呈現不同的表現量，且其蛋白含量似乎與細胞的惡性 (malignancy) 程度有關。我同時於人類神經細胞以及非神經細胞中發現一個全新的 CRMP-2 亞型 (variant)，稱為長型 CRMP-2 (the long form of CRMP-2, CRMP-2L)。我運用人類基因資料庫 (human genomic database) 推測出人類 CRMP-2L 的互補去氧核醣核酸 (cDNA) 序列，至於 CRMP-2L 於人類細胞中的實際表現情形亦以西方墨點法以及反轉錄酶-聚合酶連鎖反應法加以確認。就筆者所知，本論文為證實長型 CRMP-2 表現於人類細胞中的首次報導。
CRMP-2 為磷酸化蛋白 (phosphoprotein)。本論文中，我們在豬腦萃取物當中發現 CRMP-2 是 GSK-3 的主要受質之一。GSK-3 家族的兩種亞型 (isoform) 酵素，包括 GSK-3 及 GSK-3 皆能有效地對由豬腦中所純化出的 CRMP-2 進行磷酸化作用，且顯著地延遲 CRMP-2 在膠體電泳中的移動速度；而此一現象與愛滋海默症病患腦中 CRMP-2 的修飾作用 (modification) 很相似。有趣的是，將 SK-N-SH 神經母細胞瘤 (neuroblastoma) 細胞處以去磷酸酶 (phosphatase) 抑制劑岡田酸 (okadaic acid)，可引發 CRMP-2 產生相同的修飾作用；而若事先處理 GSK-3 抑制劑，則能完全阻斷岡田酸所引發的 CRMP-2 的修飾現象。利用核醣核酸干擾法 (RNA interference) 同時降低 (knock down) GSK-3 及 GSK-3 的蛋白質表現，可以有效地削弱岡田酸所引發的 CRMP-2 的修飾作用；然而若單一降低 GSK-3 或 GSK-3 的蛋白質表現，則無此削弱作用。我們將愛滋海默症相關的 CRMP-2 高度磷酸化作用點絲胺酸-518 (Ser-518) 以及絲胺酸-522 (Ser-522) 點突變成無法被磷酸化 (non-phosphorylatable) 的丙胺酸 (alanine)，可以完全阻斷岡田酸在 SK-N-SH 細胞中所引發的 CRMP-2 的修飾現象。由試管中實驗發現， CRMP-2 在被 GSK-3 磷酸化之前，其絲胺酸-522 必須先被 cyclin-dependent kinase 5 (Cdk5) 進行事先磷酸化 (pre-phosphorylation) 作用後才能被 GSK-3 磷酸化。然而利用 Cdk5 抑制劑 roscovitine 或是核醣核酸干擾法抑制 Cdk5 的活性，對於岡田酸在細胞中所引發的 CRMP-2 的修飾現象並無法產生明顯抑制作用。綜合上述結果，本論文首次證明岡田酸可以引發 SK-N-SH 細胞中 CRMP-2 產生與愛滋海默症相關的高度磷酸化修飾作用。在此過程，GSK-3、GSK-3 以及絲胺酸-522 激酶 (kinase) 皆參與其中。

Collapsin response mediator protein-2 (CRMP-2), a phosphoprotein involved in axonal outgrowth and microtubule dynamics, is aberrantly phosphorylated in Alzheimer disease (AD) brain. Alteration of glycogen synthase kinase-3 (GSK-3) activity is associated with the pathogenesis of AD. CRMP-2 is highly expressed in the developing nervous system. It is believed that CRMP-2 is a neuronal tissue-specific protein, however, its expression in non-neuronal cells has not been investigated clearly. Here I demonstrate that CRMP-2 is not only expressed in neuronal cells but also in non-neuronal cells by RT-PCR and Western blotting analyses. CRMP-2 is differentially expressed in different cell lines and the amount of CRMP-2 protein seems to correlate with the degree of malignancy. In addition, I also identify a novel variant of CRMP-2, the long form of CRMP-2 (CRMP-2L), in human neuronal and non-neuronal cells. Putative human CRMP-2L cDNA sequence was predicted from human genomic database and its expression in human cells was also confirmed. So far as I known, it is the first report that demonstrates the long form of CRMP-2 exist in human cells. I also provide evidence to show that CRMP-2 is one of the major substrates for GSK-3 in pig brain extracts. Both GSK-3 and 3 phosphorylate purified pig brain CRMP-2 and significantly alter it mobility in SDS-gels, resembling the CRMP-2 modification observed in AD brain. Interestingly, this modification can be detected in SK-N-SH neuroblastoma cells treated with a phosphatase inhibitor, okadaic acid (OA), and GSK-3 inhibitors completely block this OA-induced event. Knock-down of both GSK-3 and 3but not either kinase alone, impairs OA-induced modification of CRMP-2. Mutation of Ser-518 or Ser-522 of CRMP-2, which are highly phosphorylated in AD brain, to Ala blocks the OA-induced modification of CRMP-2 in SK-N-SH cells. Ser-522 prephosphorylated by Cdk5 is required for subsequent GSK-3-mediated hyperphosphorylation of CRMP-2 in vitro. However, inhibition of Cdk5 by roscovitine or siRNA pools has little effects on the OA-induced modification of CRMP-2 in cells. Collectively, our results demonstrate for the first time that OA can induce hyperphosphorylation of CRMP-2 in SK-N-SH cells at sites aberrantly phosphorylated in AD brain, and both GSK-3 and 3and Ser-522 kinase(s) are involved in this process.

指導教授推薦書
口試委員審定書
長庚大學授權書………………………………………………………. iii
誌謝……………………………………………………………………. iv
Abbreviations………………………………………………………….. v
中文摘要………………………………………………………………. vii
Abstract ……………………………………………………………….. ix
1. Introduction …………………………………………………………. 1
1.1 Glycogen synthase kinase-3 (GSK-3)…………………………… 1
1.1.1 GSK-3 isoforms …………………………………………… 1
1.1.2 GSK-3 regulation ………………………………………….. 3
1.1.3 GSK-3 substrates …………………………………………… 6
1.1.4 GSK-3 in Wnt signaling …………………………………… 7
1.1.5 GSK-3 in the regulation of cell polarity …………………… 10
1.1.6 GSK-3 in Alzheimer’s disease …………………………….. 11
1.2 Collapsin response mediator protein-2 (CRMP-2)……………… 14
1.2.1 CRMP-2 regulates growth cone collapse ………………….. 15
1.2.2 CRMP-2 in axon formation ………………………………… 15
1.2.3 Phosphorylation of CRMP-2 ………………………………. 16
1.2.4 CRMP-2 in Alzheimer’s disease …………………………… 17
2. Specific aims ……………………………………………………….. 19
3. Materials and methods ……………………………………………… 21
3.1 Materials ………………………………………………………… 21
3.2 Purification of enzymes and proteins …………………………… 21
3.3 Assay for substrate phosphorylation ……………………………. 22
3.4 Two-dimensional (2D) gel electrophoresis, in-gel
digestion of proteins and mass spectrometric analysis ………... 22
3.5 Production of anti-CRMP-2, anti-CRMP-2L,
anti-GSK-3 and anti-GSK-3 antibodies……………………. 23
3.6 Two-dimensional phosphoamino acid analysis ………………… 24
3.7 Cell culture, transfection, drug treatment,
Western blot and immunoprecipitation ………………………. 24
3.8 Plasmids construction…………………………………………… 25
3.9 Production of recombinant proteins …………………………...... 27
3.10 RNA interference and siRNA transfection…………………….. 28
3.11 Reverse transcriptase polymerase chain
reaction (RT-PCR)……………………………………………. 28
4. Results ……………………………………………………………… 30
4.1 Purification of a major substrate for GSK-3
from pig brain …………………………………………………. 30
4.2 Molecular weight shift of the purified substrates
in SDS-PAGE after phosphorylation by GSK-3 ……………..... 31
4.3 Identification of the purified substrates as
collapsin response mediator protein-2 (CRMP-2) …………….. 31
4.4 Long form of CRMP-2 (CRMP-2L) is found
in human cells ………………………………………………..... 33
4.5 CRMP-2 and CRMP-2L are expressed in both
neuronal and non-neuronal cell lines ………………………...... 35
4.6 Okadaic acid induces modification of CRMP-2
in human SK-N-SH neuroblastoma……………………………. 37
4.7 GSK-3 inhibitors prevent the OA-induced
phosphorylation of CRMP-2 in SK-N-SH cells ………………. 38
4.8 Identification of the major phosphorylation region
in CRMP-2 by GSK-3 is located in F3 segment …………….... 39
4.9 GSK-3 is as important as GSK-3 in OA-induced
modification of CRMP-2 in cells ……………………………… 40
4.10 Both Ser-522 and Ser-518 are required for OA-induced
phosphorylation-dependent mobility shift of
CRMP-2 in neuroblastoma cells …………………………….. 42
4.11 Prephosphorylation of CRMP-2 by Cdk5 is required
for subsequent GSK-3-catalyzed phosphorylation
and mobility shift of CRMP-2 in vitro ………………………. 42
4.12 Inhibition of Cdk5 is not sufficient to impair the
OA-induced modification of CRMP-2 in
SK-N-SH cells ……………………………………………….. 43
5. Discussion ………………………………………………………….. 45
6. References ………………………………………………………….. 54
7. Tables and figures ………………………………………………….. 74
8. Supplementary information ……………………………………....... 115
9. Appendix …………………………………………………………… 120

Ali, A., Hoeflich, K.P., and Woodgett, J.R. (2001). Glycogen synthase kinase-3: properties, functions, and regulation. Chem. Rev. 101, 2527-2540.
Arendt, T., Hanisch, F., Holzer, M., and Bruckner, M.K. (1994). In vivo phosphorylation in the rat basal nucleus induces PHF-like and APP immunoreactivity. Neuroreport 5, 1397-1400.
Arendt, T., Holzer, M., Fruth, R., Bruckner, M.K., and Gartner, U. (1995). Paired helical filament-like phosphorylation of tau, deposition of beta/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A. Neuroscience 69, 691-698.
Arias, C., Sharma, N., Davies, P., and Shafit-Zagardo, B. (1993). Okadaic acid induces early changes in microtubule-associated protein 2 and tau phosphorylation prior to neurodegeneration in cultured cortical neurons. J. Neurochem. 61, 673-682.
Arimura, N., Inagaki, N., Chihara, K., Menager, C., Nakamura, N., Amano, M., Iwamatsu, A., Goshima, Y., and Kaibuchi, K. (2000). Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. J. Biol. Chem. 275, 23973-23980.
Armstrong, J.L., Bonavaud, S.M., Toole, B.J., and Yeaman, S.J. (2001). Regulation of glycogen synthesis by amino acids in cultured human muscle cells. J. Biol. Chem. 276, 952-956.
Ballatore, C., Lee, V.M., and Trojanowski, J.Q. (2007). Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat. Rev. Neurosci. 8, 663-672.
Ballou, L.M., Tian, P.Y., Lin, H.Y., Jiang, Y.P., and Lin, R.Z. (2001). Dual regulation of glycogen synthase kinase-3beta by the alpha1A-adrenergic receptor. J. Biol. Chem. 276, 40910-40916.
Beals, C.R., Sheridan, C.M., Turck, C.W., Gardner, P., and Crabtree, G.R. (1997). Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 275, 1930-1934.
Benjamin, W.B., Pentyala, S.N., Woodgett, J.R., Hod, Y., and Marshak, D. (1994). ATP citrate-lyase and glycogen synthase kinase-3 beta in 3T3-L1 cells during differentiation into adipocytes. Biochem. J. 300 ( Pt 2), 477-482.
Bhat, R.V., Shanley, J., Correll, M.P., Fieles, W.E., Keith, R.A., Scott, C.W., and Lee, C.M. (2000). Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc. Natl. Acad. Sci. U. S. A 97, 11074-11079.
Bialojan, C. and Takai, A. (1988). Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics. Biochem. J. 256, 283-290.
Billingsley, M.L. and Kincaid, R.L. (1997). Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem. J. 323 ( Pt 3), 577-591.
Boyle, W.J., Smeal, T., Defize, L.H., Angel, P., Woodgett, J.R., Karin, M., and Hunter, T. (1991). Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell 64, 573-584.
Brady, M.J., Bourbonais, F.J., and Saltiel, A.R. (1998). The activation of glycogen synthase by insulin switches from kinase inhibition to phosphatase activation during adipogenesis in 3T3-L1 cells. J. Biol. Chem. 273, 14063-14066.
Brown, M., Jacobs, T., Eickholt, B., Ferrari, G., Teo, M., Monfries, C., Qi, R.Z., Leung, T., Lim, L., and Hall, C. (2004). Alpha2-chimaerin, cyclin-dependent Kinase 5/p35, and its target collapsin response mediator protein-2 are essential components in semaphorin 3A-induced growth-cone collapse. J. Neurosci. 24, 8994-9004.
Byk, T., Dobransky, T., Cifuentes-Diaz, C., and Sobel, A. (1996). Identification and molecular characterization of Unc-33-like phosphoprotein (Ulip), a putative mammalian homolog of the axonal guidance-associated unc-33 gene product. J. Neurosci. 16, 688-701.
Byk, T., Ozon, S., and Sobel, A. (1998). The Ulip family phosphoproteins. Common and specific properties. Eur. J. Biochem. 254, 14-24.
Cadigan, K.M. and Liu, Y.I. (2006). Wnt signaling: complexity at the surface. J. Cell Sci. 119, 395-402.
Chu, B., Soncin, F., Price, B.D., Stevenson, M.A., and Calderwood, S.K. (1996). Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. J. Biol. Chem. 271, 30847-30857.
Chu, Y.W., Yang, P.C., Yang, S.C., Shyu, Y.C., Hendrix, M.J., Wu, R., and Wu, C.W. (1997). Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am. J. Respir. Cell Mol. Biol. 17, 353-360.
Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell 127, 469-480.
Coghlan, M.P., Culbert, A.A., Cross, D.A., Corcoran, S.L., Yates, J.W., Pearce, N.J., Rausch, O.L., Murphy, G.J., Carter, P.S., Roxbee, C.L., Mills, D., Brown, M.J., Haigh, D., Ward, R.W., Smith, D.G., Murray, K.J., Reith, A.D., and Holder, J.C. (2000). Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem. Biol. 7, 793-803.
Cole, A.R., Causeret, F., Yadirgi, G., Hastie, C.J., McLauchlan, H., McManus, E.J., Hernandez, F., Eickholt, B.J., Nikolic, M., and Sutherland, C. (2006). Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. J. Biol. Chem. 281, 16591-16598.
Cole, A.R., Knebel, A., Morrice, N.A., Robertson, L.A., Irving, A.J., Connolly, C.N., and Sutherland, C. (2004). GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons. J. Biol. Chem. 279, 50176-50180.
Cole, A.R., Noble, W., van, A.L., Plattner, F., Meimaridou, R., Hogan,D., Taylor, M., LaFrancois, J., Gunn-Moore, F., Verkhratsky, A., Oddo, S., LaFerla, F., Giese, K.P., Dineley, K.T., Duff, K., Richardson, J.C., Yan, S.D., Hanger, D.P., Allan, S.M., and Sutherland, C. (2007). Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression. J. Neurochem. 103, 1132-1144.
Cross, D.A., Alessi, D.R., Cohen, P., Andjelkovich, M., and Hemmings, B.A. (1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785-789.
Cross, D.A., Culbert, A.A., Chalmers, K.A., Facci, L., Skaper, S.D., and Reith, A.D. (2001). Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J. Neurochem. 77, 94-102.
Dajani, R., Fraser, E., Roe, S.M., Young, N., Good, V., Dale, T.C., and Pearl, L.H. (2001). Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 105, 721-732.
Davidson, G., Wu, W., Shen, J., Bilic, J., Fenger, U., Stannek, P., Glinka, A., and Niehrs, C. (2005). Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438, 867-872.
Deibler, G.E., Stone, A.L., and Kies, M.W. (1990). Role of phosphorylation in conformational adaptability of bovine myelin basic protein. Proteins 7, 32-40.
Dent, P., Campbell, D.G., Hubbard, M.J., and Cohen, P. (1989). Multisite phosphorylation of the glycogen-binding subunit of protein phosphatase-1G by cyclic AMP-dependent protein kinase and glycogen synthase kinase-3. FEBS Lett. 248, 67-72.
Deo, R.C., Schmidt, E.F., Elhabazi, A., Togashi, H., Burley, S.K., and Strittmatter, S.M. (2004). Structural bases for CRMP function in plexin-dependent semaphorin3A signaling. EMBO J. 23, 9-22.
Diehl, J.A., Cheng, M., Roussel, M.F., and Sherr, C.J. (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499-3511.
Ding, V.W., Chen, R.H., and McCormick, F. (2000). Differential regulation of glycogen synthase kinase 3beta by insulin and Wnt signaling. J. Biol. Chem. 275, 32475-32481.
Doble, B.W. and Woodgett, J.R. (2003). GSK-3: tricks of the trade for a multi-tasking kinase. J. Cell Sci. 116, 1175-1186.
Dupont-Wallois, L., Sautiere, P.E., Cocquerelle, C., Bailleul, B., Delacourte, A., and Caillet-Boudin, M.L. (1995). Shift from fetal-type to Alzheimer-type phosphorylated Tau proteins in SKNSH-SY 5Y cells treated with okadaic acid. FEBS Lett. 357, 197-201.
Eickholt, B.J., Walsh, F.S., and Doherty, P. (2002). An inactive pool of GSK-3 at the leading edge of growth cones is implicated in Semaphorin 3A signaling. J. Cell Biol. 157, 211-217.
Eldar-Finkelman, H., Seger, R., Vandenheede, J.R., and Krebs, E.G. (1995). Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. J. Biol. Chem. 270, 987-990.
Embi, N., Rylatt, D.B., and Cohen, P. (1980). Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur. J. Biochem. 107, 519-527.
Etienne-Manneville, S. and Hall, A. (2003). Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. Nature 421, 753-756.
Fang, X., Yu, S., Tanyi, J.L., Lu, Y., Woodgett, J.R., and Mills, G.B. (2002). Convergence of multiple signaling cascades at glycogen synthase kinase 3: Edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase C-dependent intracellular pathway. Mol. Cell Biol. 22, 2099-2110.
Fang, X., Yu, S.X., Lu, Y., Bast, R.C., Jr., Woodgett, J.R., and Mills, G.B. (2000). Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc. Natl. Acad. Sci. U. S. A 97, 11960-11965.
Ferkey, D.M. and Kimelman, D. (2000). GSK-3: new thoughts on an old enzyme. Dev. Biol. 225, 471-479.
Fiol, C.J., Wang, A., Roeske, R.W., and Roach, P.J. (1990). Ordered multisite protein phosphorylation. Analysis of glycogen synthase kinase 3 action using model peptide substrates. J. Biol. Chem. 265, 6061-6065.
Fiol, C.J., Williams, J.S., Chou, C.H., Wang, Q.M., Roach, P.J., and Andrisani, O.M. (1994). A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression. J. Biol. Chem. 269, 32187-32193.
Frame, S. and Cohen, P. (2001). GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359, 1-16.
Frame, S., Cohen, P., and Biondi, R.M. (2001). A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell 7, 1321-1327.
Fukata, Y., Itoh, T.J., Kimura, T., Menager, C., Nishimura, T., Shiromizu, T., Watanabe, H., Inagaki, N., Iwamatsu, A., Hotani, H., and Kaibuchi, K. (2002). CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat. Cell Biol. 4, 583-591.
Furiya, Y., Sahara, N., and Mori, H. (1993). Okadaic acid enhances abnormal phosphorylation on tau proteins. Neurosci. Lett. 156, 67-69.
Garrido, J.J., Simon, D., Varea, O., and Wandosell, F. (2007). GSK3 alpha and GSK3 beta are necessary for axon formation. FEBS Lett. 581, 1579-1586.
Goedert, M., Wischik, C.M., Crowther, R.A., Walker, J.E., and Klug, A. (1988). Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. U. S. A 85, 4051-4055.
Gong, C.X., Lidsky, T., Wegiel, J., Zuck, L., Grundke-Iqbal, I., and 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.
Gong, C.X., Singh, T.J., Grundke-Iqbal, I., and Iqbal, K. (1993). Phosphoprotein phosphatase activities in Alzheimer disease brain. J. Neurochem. 61, 921-927.
Goold, R.G., Owen, R., and Gordon-Weeks, P.R. (1999). Glycogen synthase kinase 3beta phosphorylation of microtubule-associated protein 1B regulates the stability of microtubules in growth cones. J. Cell Sci. 112 ( Pt 19), 3373-3384.
Goshima, Y., Nakamura, F., Strittmatter, P., and Strittmatter, S.M. (1995). Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 376, 509-514.
Grundke-Iqbal, I., Iqbal, K., Tung, Y.C., Quinlan, M., Wisniewski, H.M., and Binder, L.I. (1986). Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U. S. A 83, 4913-4917.
Gu, Y., Hamajima, N., and Ihara, Y. (2000). Neurofibrillary tangle-associated collapsin response mediator protein-2 (CRMP-2) is highly phosphorylated on Thr-509, Ser-518, and Ser-522. Biochemistry 39, 4267-4275.
Gu, Y. and Ihara, Y. (2000). Evidence that collapsin response mediator protein-2 is involved in the dynamics of microtubules. J. Biol. Chem. 275, 17917-17920.
Hall, C., Brown, M., Jacobs, T., Ferrari, G., Cann, N., Teo, M., Monfries, C., and Lim, L. (2001). Collapsin response mediator protein switches RhoA and Rac1 morphology in N1E-115 neuroblastoma cells and is regulated by Rho kinase. J. Biol. Chem. 276, 43482-43486.
Hamajima, N., Matsuda, K., Sakata, S., Tamaki, N., Sasaki, M., and Nonaka, M. (1996). A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distribution. Gene 180, 157-163.
Hanger, D.P., Hughes, K., Woodgett, J.R., Brion, J.P., and Anderton, B.H. (1992). Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci. Lett. 147, 58-62.
Hardy, J. (2006). A hundred years of Alzheimer's disease research. Neuron 52, 3-13.
Hardy, J. and Selkoe, D.J. (2002). The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356.
Hart, M., Concordet, J.P., Lassot, I., Albert, I., del los, S.R., Durand, H., Perret, C., Rubinfeld, B., Margottin, F., Benarous, R., and Polakis, P. (1999). The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr. Biol. 9, 207-210.
Hartigan, J.A. and Johnson, G.V. (1999). Transient increases in intracellular calcium result in prolonged site-selective increases in Tau phosphorylation through a glycogen synthase kinase 3beta-dependent pathway. J. Biol. Chem. 274, 21395-21401.
Hasegawa, M., Morishima-Kawashima, M., Takio, K., Suzuki, M., Titani, K., and Ihara, Y. (1992). Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain. J. Biol. Chem. 267, 17047-17054.
He, X., Saint-Jeannet, J.P., Woodgett, J.R., Varmus, H.E., and Dawid, I.B. (1995). Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature 374, 617-622.
Hedgecock, E.M., Culotti, J.G., Thomson, J.N., and Perkins, L.A. (1985). Axonal guidance mutants of Caenorhabditis elegans identified by filling sensory neurons with fluorescein dyes. Dev. Biol. 111, 158-170.
Hemmings, B.A., Yellowlees, D., Kernohan, J.C., and Cohen, P. (1981). Purification of glycogen synthase kinase 3 from rabbit skeletal muscle. Copurification with the activating factor (FA) of the (Mg-ATP) dependent protein phosphatase. Eur. J. Biochem. 119, 443-451.
Herzog, W. and Weber, K. (1978). Fractionation of brain microtubule-associated proteins. Isolation of two different proteins which stimulate tubulin polymerization in vitro. Eur. J. Biochem. 92, 1-8.
Hewitt, R.E., McMarlin, A., Kleiner, D., Wersto, R., Martin, P., Tsokos, M., Stamp, G.W., and Stetler-Stevenson, W.G. (2000). Validation of a model of colon cancer progression. J. Pathol. 192, 446-454.
Hill, J.J., Callaghan, D.A., Ding, W., Kelly, J.F., and Chakravarthy, B.R. (2006). Identification of okadaic acid-induced phosphorylation events by a mass spectrometry approach. Biochem. Biophys. Res. Commun. 342, 791-799.
Hinoi, T., Yamamoto, H., Kishida, M., Takada, S., Kishida, S., and Kikuchi, A. (2000). Complex formation of adenomatous polyposis coli gene product and axin facilitates glycogen synthase kinase-3 beta-dependent phosphorylation of beta-catenin and down-regulates beta-catenin. J. Biol. Chem. 275, 34399-34406.
Hoeflich, K.P., Luo, J., Rubie, E.A., Tsao, M.S., Jin, O., and Woodgett, J.R. (2000). Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 406, 86-90.
Hooper, C., Killick, R., and Lovestone, S. (2008). The GSK3 hypothesis of Alzheimer's disease. J. Neurochem. 104, 1433-1439.
Hoshi, M., Sato, M., Kondo, S., Takashima, A., Noguchi, K., Takahashi, M., Ishiguro, K., and Imahori, K. (1995). Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria. J. Biochem. 118, 683-685.
Huang, H. and He, X. (2008). Wnt/beta-catenin signaling: new (and old) players and new insights. Curr. Opin. Cell Biol. 20, 119-125.
Hughes, K., Nikolakaki, E., Plyte, S.E., Totty, N.F., and Woodgett, J.R. (1993). Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 12, 803-808.
Hughes, K., Pulverer, B.J., Theocharous, P., and Woodgett, J.R. (1992a). Baculovirus-mediated expression and characterisation of rat glycogen synthase kinase-3 beta, the mammalian homologue of the Drosophila melanogaster zeste-white 3sgg homeotic gene product. Eur. J. Biochem. 203, 305-311.
Hughes, K., Ramakrishna, S., Benjamin, W.B., and Woodgett, J.R. (1992b). Identification of multifunctional ATP-citrate lyase kinase as the alpha-isoform of glycogen synthase kinase-3. Biochem. J. 288 ( Pt 1), 309-314.
Ihara, Y., Nukina, N., Miura, R., and Ogawara, M. (1986). Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J. Biochem. 99, 1807-1810.
Ikeda, S., Kishida, S., Yamamoto, H., Murai, H., Koyama, S., and Kikuchi, A. (1998). Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 17, 1371-1384.
Imahori, K. and Uchida, T. (1997). Physiology and pathology of tau protein kinases in relation to Alzheimer's disease. J. Biochem. 121, 179-188.
Inagaki, N., Chihara, K., Arimura, N., Menager, C., Kawano, Y., Matsuo, N., Nishimura, T., Amano, M., and Kaibuchi, K. (2001). CRMP-2 induces axons in cultured hippocampal neurons. Nat. Neurosci. 4, 781-782.
Inatome, R., Tsujimura, T., Hitomi, T., Mitsui, N., Hermann, P., Kuroda, S., Yamamura, H., and Yanagi, S. (2000). Identification of CRAM, a novel unc-33 gene family protein that associates with CRMP3 and protein-tyrosine kinase(s) in the developing rat brain. J. Biol. Chem. 275, 27291-27302.
Ishiguro, K., Shiratsuchi, A., Sato, S., Omori, A., Arioka, M., Kobayashi, S., Uchida, T., and 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.
Ito, T., Kagoshima, M., Sasaki, Y., Li, C., Udaka, N., Kitsukawa, T., Fujisawa, H., Taniguchi, M., Yagi, T., Kitamura, H., and Goshima, Y. (2000). Repulsive axon guidance molecule Sema3A inhibits branching morphogenesis of fetal mouse lung. Mech. Dev. 97, 35-45.
Jiang, H., Guo, W., Liang, X., and Rao, Y. (2005). Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell 120, 123-135.
Jope, R.S. and Johnson, G.V. (2004). The glamour and gloom of glycogen synthase kinase-3. Trends Biochem. Sci. 29, 95-102.
Kawano, Y., Yoshimura, T., Tsuboi, D., Kawabata, S., Kaneko-Kawano, T., Shirataki, H., Takenawa, T., and Kaibuchi, K. (2005). CRMP-2 is involved in kinesin-1-dependent transport of the Sra-1/WAVE1 complex and axon formation. Mol. Cell Biol. 25, 9920-9935.
Kim, D., Su, J., and Cotman, C.W. (1999a). Sequence of neurodegeneration and accumulation of phosphorylated tau in cultured neurons after okadaic acid treatment. Brain Res. 839, 253-262.
Kim, L., Liu, J., and Kimmel, A.R. (1999b). The novel tyrosine kinase ZAK1 activates GSK3 to direct cell fate specification. Cell 99, 399-408.
Kimura, T., Watanabe, H., Iwamatsu, A., and Kaibuchi, K. (2005). Tubulin and CRMP-2 complex is transported via Kinesin-1. J. Neurochem. 93, 1371-1382.
Kirschenbaum, F., Hsu, S.C., Cordell, B., and McCarthy, J.V. (2001). Glycogen synthase kinase-3beta regulates presenilin 1 C-terminal fragment levels. J. Biol. Chem. 276, 30701-30707.
Kitamura, K., Takayama, M., Hamajima, N., Nakanishi, M., Sasaki, M., Endo, Y., Takemoto, T., Kimura, H., Iwaki, M., and Nonaka, M. (1999). Characterization of the human dihydropyrimidinase-related protein 2 (DRP-2) gene. DNA Res. 6, 291-297.
Klafki, H.W., Staufenbiel, M., Kornhuber, J., and Wiltfang, J. (2006). Therapeutic approaches to Alzheimer's disease. Brain 129, 2840-2855.
Klein, P.S. and Melton, D.A. (1996). A molecular mechanism for the effect of lithium on development. Proc. Natl. Acad. Sci. U. S. A 93, 8455-8459.
Kobayashi, N. and Mundel, P. (1998). A role of microtubules during the formation of cell processes in neuronal and non-neuronal cells. Cell Tissue Res. 291, 163-174.
Kosik, K.S., Duffy, L.K., Dowling, M.M., Abraham, C., McCluskey, A., and Selkoe, D.J. (1984). Microtubule-associated protein 2: monoclonal antibodies demonstrate the selective incorporation of certain epitopes into Alzheimer neurofibrillary tangles. Proc. Natl. Acad. Sci. U. S. A 81, 7941-7945.
Krause, U., Bertrand, L., Maisin, L., Rosa, M., and Hue, L. (2002). Signalling pathways and combinatory effects of insulin and amino acids in isolated rat hepatocytes. Eur. J. Biochem. 269, 3742-3750.
LaFerla, F.M., Green, K.N., and Oddo, S. (2007). Intracellular amyloid-beta in Alzheimer's disease. Nat. Rev. Neurosci. 8, 499-509.
Lau, K.F., Miller, C.C., Anderton, B.H., and Shaw, P.C. (1999). Expression analysis of glycogen synthase kinase-3 in human tissues. J. Pept. Res. 54, 85-91.
Lee, V.M., Balin, B.J., Otvos, L. Jr., and Trojanowski, J.Q. (1991). A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251, 675-678.
Lee, V.M., Goedert, M., and Trojanowski, J.Q. (2001). Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121-1159.
Lesort, M., Jope, R.S., and Johnson, G.V. (1999). Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3beta and Fyn tyrosine kinase. J. Neurochem. 72, 576-584.
Leung, T., Ng, Y., Cheong, A., Ng, C.H., Tan, I., Hall, C., and Lim, L. (2002). p80 ROKalpha binding protein is a novel splice variant of CRMP-1 which associates with CRMP-2 and modulates RhoA-induced neuronal morphology. FEBS Lett. 18, 445-449.
Jho, E., Lomvardas, S., and Costantini, F. (1999). A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression. Biochem. Biophys. Res. Commun. 266, 28-35.
Li, L., Yuan, H., Weaver, C.D., Mao, J., Farr, G.H. III, Sussman, D.J., Jonkers, J., Kimelman, D., and Wu, D. (1999). Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. EMBO J. 18, 4233-4240.
Li, M., Wang, X., Meintzer, M.K., Laessig, T., Birnbaum, M.J., and Heidenreich, K.A. (2000). Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta. Mol. Cell Biol. 20, 9356-9363.
Lichtenberg-Kraag, B., Mandelkow, E.M., Biernat, J., Steiner, B., Schroter, C., Gustke, N., Meyer, H.E., and Mandelkow, E. (1992). Phosphorylation-dependent epitopes of neurofilament antibodies on tau protein and relationship with Alzheimer tau. Proc. Natl. Acad. Sci. U. S. A 89, 5384-5388.
Liu, C., Li, Y., Semenov, M., Han, C., Baeg, G.H., Tan, Y., Zhang, Z., Lin, X., and He, X. (2002). Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837-847.
MacAulay, K., Doble, B.W., Patel, S., Hansotia, T., Sinclair, E.M., Drucker, D.J., Nagy, A., and Woodgett, J.R. (2007). Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism. Cell Metab 6, 329-337.
Malchiodi-Albedi, F., Petrucci, T.C., Picconi, B., Iosi, F., and Falchi, M. (1997). Protein phosphatase inhibitors induce modification of synapse structure and tau hyperphosphorylation in cultured rat hippocampal neurons. J. Neurosci. Res. 48, 425-438.
Mandelkow, E.M., Drewes, G., Biernat, J., Gustke, N., Van, L.J., Vandenheede, J.R., and Mandelkow, E. (1992). Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett. 314, 315-321.
Mao, J., Wang, J., Liu, B., Pan, W., Farr, G.H. III, Flynn, C., Yuan, H., Takada, S., Kimelman, D., Li, L., and Wu, D. (2001). Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol. Cell 7, 801-809.
Martenson, R.E., Law, M.J., and Deibler, G.E. (1983). Identification of multiple in vivo phosphorylation sites in rabbit myelin basic protein. J. Biol. Chem. 258, 930-937.
Meijer, L., Borgne, A., Mulner, O., Chong, J.P., Blow, J.J., Inagaki, N., Inagaki, M., Delcros, J.G., and Moulinoux, J.P. (1997). Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 243, 527-536.
Minturn, J.E., Fryer, H.J., Geschwind, D.H., and Hockfield, S. (1995). TOAD-64, a gene expressed early in neuronal differentiation in the rat, is related to unc-33, a C. elegans gene involved in axon outgrowth. J. Neurosci. 15, 6757-6766.
Morfini, G., Szebenyi, G., Elluru, R., Ratner, N., and Brady, S.T. (2002). Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J. 21, 281-293.
Munoz-Montano, J.R., Moreno, F.J., Avila, J., and az-Nido, J. (1997). Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons. FEBS Lett. 411, 183-188.
Nishimura, T., Fukata, Y., Kato, K., Yamaguchi, T., Matsuura, Y., Kamiguchi, H., and Kaibuchi, K. (2003). CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth. Nat. Cell Biol. 5, 819-826.
Park, I.K., Roach, P., Bondor, J., Fox, S.P., and DePaoli-Roach, A.A. (1994). Molecular mechanism of the synergistic phosphorylation of phosphatase inhibitor-2. Cloning, expression, and site-directed mutagenesis of inhibitor-2. J. Biol. Chem. 269, 944-954.
Pei, J.J., Braak, E., Braak, H., Grundke-Iqbal, I., Iqbal, K., Winblad, B., and Cowburn, R.F. (1999). Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J. Neuropathol. Exp. Neurol. 58, 1010-1019.
Pei, J.J., Tanaka, T., Tung, Y.C., Braak, E., Iqbal, K., and Grundke-Iqbal, I. (1997). Distribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain. J. Neuropathol. Exp. Neurol. 56, 70-78.
Perry, G., Rizzuto, N., utilio-Gambetti, L., and Gambetti, P. (1985). Paired helical filaments from Alzheimer disease patients contain cytoskeletal components. Proc. Natl. Acad. Sci. U. S. A 82, 3916-3920.
Phiel, C.J., Wilson, C.A., Lee, V.M., and Klein, P.S. (2003). GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature 423, 435-439.
Polakis, P. (2007). The many ways of Wnt in cancer. Curr. Opin. Genet. Dev. 17, 45-51.
Quinn, C.C., Chen, E., Kinjo, T.G., Kelly, G., Bell, A.W., Elliott, R.C., McPherson, P.S., and Hockfield, S. (2003). TUC-4b, a novel TUC family variant, regulates neurite outgrowth and associates with vesicles in the growth cone. J. Neurosci. 23, 2815-2823.
Quinn,C.C., Gray,G.E., and Hockfield,S. (1999). A family of proteins implicated in axon guidance and outgrowth. J. Neurobiol. 41, 158-164.
Ramakrishna, S., D'Angelo, G., and Benjamin, W.B. (1990). Sequence of sites on ATP-citrate lyase and phosphatase inhibitor 2 phosphorylated by multifunctional protein kinase (a glycogen synthase kinase 3 like kinase). Biochemistry 29, 7617-7624.
Rubinfeld, B., Albert, I., Porfiri, E., Fiol, C., Munemitsu, S., and Polakis, P. (1996). Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science 272, 1023-1026.
Ryan, K.A. and Pimplikar, S.W. (2005). Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain. J. Cell Biol. 171, 327-335.
Saito,Y., Vandenheede,J.R., and Cohen,P. (1994). The mechanism by which epidermal growth factor inhibits glycogen synthase kinase 3 in A431 cells. Biochem. J. 303 ( Pt 1), 27-31.
Schmidt, E.F. and Strittmatter, S.M. (2007). The CRMP family of proteins and their role in Sema3A signaling. Adv. Exp. Med. Biol. 600, 1-11.
Sears, R., Nuckolls, F., Haura, E., Taya, Y., Tamai, K., and Nevins, J.R. (2000). Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 14, 2501-2514.
Seidensticker, M.J. and Behrens, J. (2000). Biochemical interactions in the wnt pathway. Biochim. Biophys. Acta 1495, 168-182.
Shaw, M., Cohen, P., and Alessi, D.R. (1997). Further evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 and not by dephosphorylation of Tyr-216. FEBS Lett. 416, 307-311.
Stambolic, V. and Woodgett, J.R. (1994). Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem. J. 303 ( Pt 3), 701-704.
Sternberger, N.H., Sternberger, L.A., and Ulrich, J. (1985). Aberrant neurofilament phosphorylation in Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A 82, 4274-4276.
Tahimic, C.G., Tomimatsu, N., Nishigaki, R., Fukuhara, A., Toda, T., Kaibuchi, K., Shiota, G., Oshimura, M., and Kurimasa, A. (2006). Evidence for a role of Collapsin response mediator protein-2 in signaling pathways that regulate the proliferation of non-neuronal cells. Biochem. Biophys. Res. Commun. 340, 1244-1250.
Tanji, C., Yamamoto, H., Yorioka, N., Kohno, N., Kikuchi, K., and Kikuchi, A. (2002). A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta ) and mediates protein kinase A-dependent inhibition of GSK-3beta. J. Biol. Chem. 277, 36955-36961.
ter Haar, E., Coll, J.T., Austen, D.A., Hsiao, H.M., Swenson, L., and Jain, J. (2001). Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat. Struct. Biol. 8, 593-596.
Terruzzi, I., Allibardi, S., Bendinelli, P., Maroni, P., Piccoletti, R., Vesco, F., Samaja, M., and Luzi, L. (2002). Amino acid- and lipid-induced insulin resistance in rat heart: molecular mechanisms. Mol. Cell Endocrinol. 190, 135-145.
Tsai, I.C., Hsieh, Y.J., Lyu, P.C., and Yu, J.S. (2005). Anti-phosphopeptide antibody, P-STM as a novel tool for detecting mitotic phosphoproteins: identification of lamins A and C as two major targets. J. Cell Biochem. 94, 967-981.
Uchida, Y., Ohshima, T., Sasaki, Y., Suzuki, H., Yanai, S., Yamashita, N., Nakamura, F., Takei, K., Ihara, Y., Mikoshiba, K., Kolattukudy, P., Honnorat, J., and Goshima, Y. (2005). Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease. Genes Cells 10, 165-179.
van Amerongen, R. and Berns, A. (2005). Re-evaluating the role of Frat in Wnt-signal transduction. Cell Cycle 4, 1065-1072.
van Amerongen, R., Nawijn, M., Franca-Koh, J., Zevenhoven, J., van der, G.H., Jonkers, J., and Berns, A. (2005). Frat is dispensable for canonical Wnt signaling in mammals. Genes Dev. 19, 425-430.
Vandenheede, J.R., Yang, S.D., Goris, J., and Merlevede, W. (1980). ATP x Mg-dependent protein phosphatase from rabbit skeletal muscle. II. Purification of the activating factor and its characterization as a bifunctional protein also displaying synthase kinase activity. J. Biol. Chem. 255, 11768-11774.
Viatour, P., Dejardin, E., Warnier, M., Lair, F., Claudio, E., Bureau, F., Marine, J.C., Merville, M.P., Maurer, U., Green, D., Piette, J., Siebenlist, U., Bours, V., and Chariot, A. (2004). GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity. Mol. Cell 16, 35-45.
Vincent, P., Collette, Y., Marignier, R., Vuaillat, C., Rogemond, V., Davoust, N., Malcus, C., Cavagna, S., Gessain, A., Machuca-Gayet, I., Belin, M.F., Quach, T., and Giraudon, P. (2005). A role for the neuronal protein collapsin response mediator protein 2 in T lymphocyte polarization and migration. J. Immunol. 175, 7650-7660.
Wang, J., Tung, Y.C., Wang, Y., Li, X.T., Iqbal, K., and Grundke-Iqbal, I. (2001). Hyperphosphorylation and accumulation of neurofilament proteins in Alzheimer disease brain and in okadaic acid-treated SY5Y cells. FEBS Lett. 507, 81-87.
Wang, J.Z., Wu, Q., Smith, A., Grundke-Iqbal, I., and 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.
Wang, L.H. and Strittmatter, S.M. (1996). A family of rat CRMP genes is differentially expressed in the nervous system. J. Neurosci. 16, 6197-6207.
Weingarten, M.D., Lockwood, A.H., Hwo, S.Y., and Kirschner, M.W. (1975). A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. U. S. A 72, 1858-1862.
Welcker, M., Singer, J., Loeb, K.R., Grim, J., Bloecher, A., Gurien-West, M., Clurman, B.E., and Roberts, J.M. (2003). Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation. Mol. Cell 12, 381-392.
Welsh, G.I., Miller, C.M., Loughlin, A.J., Price, N.T., and Proud, C.G. (1998). Regulation of eukaryotic initiation factor eIF2B: glycogen synthase kinase-3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS Lett. 421, 125-130.
Welsh, G.I. and Proud, C.G. (1993). Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem. J. 294 ( Pt 3), 625-629.
Willert, K., Brown, J.D., Danenberg, E., Duncan, A.W., Weissman, I.L., Reya, T., Yates, J.R. III, and Nusse, R. (2003). Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448-452.
Woodgett, J.R. (1990). Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 9, 2431-2438.
Woodgett, J.R. (1991). cDNA cloning and properties of glycogen synthase kinase-3. Methods Enzymol. 200, 564-577.
Woodgett, J.R. (2001). Judging a protein by more than its name: GSK-3. Sci. STKE. 2001, RE12.
Woods, Y.L., Cohen, P., Becker, W., Jakes, R., Goedert, M., Wang, X., and Proud, C.G. (2001). The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem. J. 355, 609-615.
Wu, C.C., Chen, H.C., Chen, S.J., Liu, H.P., Hsieh, Y.Y., Yu, C.J., Tang, R., Hsieh, L.L., Yu, J.S., and Chang, Y.S. (2008). Identification of collapsin response mediator protein-2 as a potential marker of colorectal carcinoma by comparative analysis of cancer cell secretomes. Proteomics 8, 316-332.
Wu, C.C., Chien, K.Y., Tsang, N.M., Chang, K.P., Hao, S.P., Tsao, C.H., Chang, Y.S., and Yu, J.S. (2005). Cancer cell-secreted proteomes as a basis for searching potential tumor markers: nasopharyngeal carcinoma as a model. Proteomics. 5, 3173-3182.
Xu, Y.F., Zhang, Y.J., Zhang, A.H., Zhang, Q., Wu, T., and Wang, J.Z. (2004). Attenuation of okadaic acid-induced hyperphosphorylation of cytoskeletal proteins by heat preconditioning and its possible underlying mechanisms. Cell Stress. Chaperones. 9, 304-312.
Yamaguchi, H., Ishiguro, K., Uchida, T., Takashima, A., Lemere, C.A., and Imahori, K. (1996). Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol. 92, 232-241.
Yamamoto, H., Kishida, S., Kishida, M., Ikeda, S., Takada, S., and Kikuchi, A. (1999). Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J. Biol. Chem. 274, 10681-10684.
Yang, S.D. (1986). Identification of the ATP.Mg-dependent protein phosphatase activator (FA) as a myelin basic protein kinase in the brain. J. Biol. Chem. 261, 11786-11791.
Yang, S.D., Chan, W.H., and Liu, H.W. (1993a). Cyclic modulation of cytoskeleton assembly-disassembly by the ATP.Mg-dependent protein phosphatase activator (kinase FA). Biochem. Biophys. Res. Commun. 193, 1202-1210.
Yang, S.D., Song, J.S., Hsieh, Y.T., Chan, W.H., and Liu, H.W. (1992a). Cyclic inhibition-potentiation of the crosslinking of synapsin I with brain microtubules by protein kinase FA (an activator of ATP.Mg-dependent protein phosphatase). Biochem. Biophys. Res. Commun. 184, 973-979.
Yang, S.D., Song, J.S., Hsieh, Y.T., Liu, H.W., and Chan, W.H. (1992b). Identification of the ATP.Mg-dependent protein phosphatase activator (FA) as a synapsin I kinase that inhibits cross-linking of synapsin I with brain microtubules. J. Protein Chem. 11, 539-546.
Yang, S.D., Song, J.S., Liu, H.W., and Chan, W.H. (1993b). Cyclic modulation of cross-linking interactions of microtubule-associated protein-2 with actin and microtubules by protein kinase FA. J. Protein Chem. 12, 393-402.
Yang, S.D., Song, J.S., Yu, J.S., and Shiah, S.G. (1993c). Protein kinase FA/GSK-3 phosphorylates tau on Ser235-Pro and Ser404-Pro that are abnormally phosphorylated in Alzheimer's disease brain. J. Neurochem. 61, 1742-1747.
Yang, S.D., Vandenheede, J.R., Goris, J., and Merlevede, W. (1980). ATP x Mg-dependent protein phosphatase from rabbit skeletal muscle. I. Purification of the enzyme and its regulation by the interaction with an activating protein factor. J. Biol. Chem. 255, 11759-11767.
Yang, S.D., Yu, J.S., and Hua, C.W. (1990). On the mechanism of activation of protein kinase FA (an activating factor of ATP.Mg-dependent protein phosphatase) in brain myelin. J. Protein Chem. 9, 75-82.
Yang, S.D., Yu, J.S., and Lai, Y.G. (1991). Identification and characterization of the ATP.Mg-dependent protein phosphatase activator (FA) as a microtubule protein kinase in the brain. J. Protein Chem. 10, 171-181.
Yang, S.D., Yu, J.S., Shiah, S.G., and Huang, J.J. (1994). Protein kinase FA/glycogen synthase kinase-3 alpha after heparin potentiation phosphorylates tau on sites abnormally phosphorylated in Alzheimer's disease brain. J. Neurochem. 63, 1416-1425.
Yeh, C.W., Huang, S.S., Lee, R.P., and Yung, B.Y. (2006). Ras-dependent recruitment of c-Myc for transcriptional activation of nucleophosmin/B23 in highly malignant U1 bladder cancer cells. Mol. Pharmacol. 70, 1443-1453.
Yoon, S.Y., Choi, J.E., Huh, J.W., Hwang, O., Nam, H.H., and Kim, D. (2005). Inactivation of GSK-3beta in okadaic acid-induced neurodegeneration: relevance to Alzheimer's disease. Neuroreport 16, 223-227.
Yoshida, H., Watanabe, A., and Ihara, Y. (1998). Collapsin response mediator protein-2 is associated with neurofibrillary tangles in Alzheimer's disease. J. Biol. Chem. 273, 9761-9768.
Yoshimura, T., Arimura, N., and Kaibuchi, K. (2006). Signaling networks in neuronal polarization. J. Neurosci. 26, 10626-10630.
Yoshimura, T., Kawano, Y., Arimura, N., Kawabata, S., Kikuchi, A., and Kaibuchi, K. (2005). GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120, 137-149.
Yost, C., Farr, G.H. III, Pierce, S.B., Ferkey, D.M., Chen, M.M., and Kimelman, D. (1998). GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis. Cell 93, 1031-1041.
Yost, C., Torres, M., Miller, J.R., Huang, E., Kimelman, D., and Moon, R.T. (1996). The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 10, 1443-1454.
Yu, J.S., Chen, H.C., and Yang, S.D. (1997). Reversible tyrosine phosphorylation/dephosphorylation of proline-directed protein kinase FA/glycogen synthase kinase-3alpha in A431 cells. J. Cell Physiol. 171, 95-103.
Yu, J.S., Chen, W.J., Ni, M.H., Chan, W.H., and Yang, S.D. (1998). Identification of the regulatory autophosphorylation site of autophosphorylation-dependent protein kinase (auto-kinase). Evidence that auto-kinase belongs to a member of the p21-activated kinase family. Biochem. J. 334 ( Pt 1), 121-131.
Yu, J.S. and Yang, S.D. (1994a). Protein kinase FA/glycogen synthase kinase-3 predominantly phosphorylates the in vivo site Thr97-Pro in brain myelin basic protein: evidence for Thr-Pro and Ser-Arg-X-X-Ser as consensus sequence motifs. J. Neurochem. 62, 1596-1603.
Yu, J.S. and Yang, S.D. (1994b). Okadaic acid, a serine/threonine phosphatase inhibitor, induces tyrosine dephosphorylation/inactivation of protein kinase FA/GSK-3 alpha in A431 cells. J. Biol. Chem. 269, 14341-14344.
Yu, J.S. and Yang, S.D. (1994c). Tyrosine dephosphorylation and concurrent inactivation of protein kinase FA/GSK-3 alpha by genistein in A431 cells. J. Cell Biochem. 56, 131-141.
Yu, J.S. and Yang, S.D. (1993a). Identification and characterization of protein kinase FA/glycogen synthase kinase 3 in clathrin-coated brain vesicles. J. Neurochem. 60, 1714-1721.
Yu, J.S. and Yang, S.D. (1993b). Immunological and biochemical study on tissue and subcellular distributions of protein kinase FA (an activating factor of ATP.Mg-dependent protein phosphatase): a simplified and efficient procedure for high quantity purification from brain. J. Protein Chem. 12, 667-676.
Yuasa-Kawada, J., Suzuki, R., Kano, F., Ohkawara, T., Murata, M., and Noda, M. (2003). Axonal morphogenesis controlled by antagonistic roles of two CRMP subtypes in microtubule organization. Eur J Neurosci. 17, 2329-2343.
Zeng, X., Tamai, K., Doble, B., Li, S., Huang, H., Habas, R., Okamura, H., Woodgett, J.R., and He,X. (2005). A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438, 873-877.
Zhou, B.P., Deng, J., Xia, W., Xu, J., Li, Y.M., Gunduz, M., and Hung, M.C. (2004). Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat. Cell Biol. 6, 931-940.
Zumbrunn, J., Kinoshita, K., Hyman, A.A., and Nathke, I.S. (2001). Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 beta phosphorylation. Curr. Biol. 11, 44-49.