Abstract
Protein phosphorylation is a ubiquitous protein post-translational modification, which plays an important role in cellular signaling systems underlying various physiological and pathological processes. Current in silico methods mainly focused on the prediction of phosphorylation sites, but rare methods considered whether a phosphorylation site is functional or not. Since functional phosphorylation sites are more valuable for further experimental research and a proportion of phosphorylation sites have no direct functional effects, the prediction of functional phosphorylation sites is quite necessary for this research area. Previous studies have shown that functional phosphorylation sites are more conserved than non-functional phosphorylation sites in evolution. Thus, in our method, we developed a web server by integrating existing phosphorylation site prediction methods, as well as both absolute and relative evolutionary conservation scores to predict the most likely functional phosphorylation sites. Using our method, we predicted the most likely functional sites of the human, rat and mouse proteomes and built a database for the predicted sites. By the analysis of overall prediction results, we demonstrated that protein phosphorylation plays an important role in all the enriched KEGG pathways. By the analysis of protein-specific prediction results, we demonstrated the usefulness of our method for individual protein studies. Our method would help to characterize the most likely functional phosphorylation sites for further studies in this research area.
Keywords: protein, phosphorylation, function, conservation, evolution
Footnotes
These authors contributed equally to the work.
Contributor Information
Guoqing Zhang, Email: gqzhang@scbit.org.
Yixue Li, Email: yxli@sibs.ac.cn.
References
- Acosta-Jaquez H.A., Keller J.A., Foster K.G., Ekim B., Soliman G.A., Feener E.P., Ballif B.A., Fingar D.C. Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth. Mol Cell Biol. 2009;29:4308–4324. doi: 10.1128/MCB.01665-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Adachi S., Yasuda I., Nakashima M., Yamauchi T., Yamauchi J., Natsume H., Moriwaki H., Kozawa O. HSP90 inhibitors induce desensitization of EGF receptor via p38 MAPK-mediated phosphorylation at Ser1046/1047 in human pancreatic cancer cells. Oncol Rep. 2010;23:1709–1714. doi: 10.3892/or_00000815. [DOI] [PubMed] [Google Scholar]
- Aguirre V., Werner E.D., Giraud J., Lee Y.H., Shoelson S.E., White M.F. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002;277:1531–1537. doi: 10.1074/jbc.M101521200. [DOI] [PubMed] [Google Scholar]
- Alevriadou B.R. CAMs and Rho small GTPases: gatekeepers for leukocyte transendothelial migration. Focus on “VCAM-1-mediated Rac signaling controls endothelial cell-cell contacts and leukocyte transmigration”. Am J Physiol Cell Physiol. 2003;285:C250–252. doi: 10.1152/ajpcell.00189.2003. [DOI] [PubMed] [Google Scholar]
- Allingham M.J., van Buul J.D., Burridge K. ICAM-1-mediated, Src- and Pyk2-dependent vascular endothelial cadherin tyrosine phosphorylation is required for leukocyte transendothelial migration. J Immunol. 2007;179:4053–4064. doi: 10.4049/jimmunol.179.6.4053. [DOI] [PubMed] [Google Scholar]
- Altomare D.A., Wang H.Q., Skele K.L., De Rienzo A., Klein-Szanto A.J., Godwin A.K., Testa J.R. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene. 2004;23:5853–5857. doi: 10.1038/sj.onc.1207721. [DOI] [PubMed] [Google Scholar]
- Andreozzi F., Laratta E., Sciacqua A., Perticone F., Sesti G. Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells. Circ Res. 2004;94:1211–1218. doi: 10.1161/01.RES.0000126501.34994.96. [DOI] [PubMed] [Google Scholar]
- Andriopoulou P., Navarro P., Zanetti A., Lampugnani M.G., Dejana E. Histamine induces tyrosine phosphorylation of endothelial cell-to-cell adherens junctions. Arterioscl Throm Vas. 1999;19:2286–2297. doi: 10.1161/01.atv.19.10.2286. [DOI] [PubMed] [Google Scholar]
- Anfinogenova Y., Wang R.P., Li Q.F., Spinelli A.M., Tang D.D. Important role of Abelson tyrosine kinase (Abl) in regulating vascular smooth muscle contraction. Faseb J. 2007;21:A1299–A1300. [Google Scholar]
- Aono S., Hirai Y. Phosphorylation of claudin-4 is required for tight junction formation in a human keratinocyte cell line. Exp Cell Res. 2008;314:3326–3339. doi: 10.1016/j.yexcr.2008.08.012. [DOI] [PubMed] [Google Scholar]
- Arai S., Matsushita A., Du K., Yagi K., Okazaki Y., Kurokawa R. Novel homeodomain-interacting protein kinase family member, HIPK4, phosphorylates human p53 at serine 9. FEBS Lett. 2007;581:5649–5657. doi: 10.1016/j.febslet.2007.11.022. [DOI] [PubMed] [Google Scholar]
- Arber S., Barbayannis F.A., Hanser H., Schneider C., Stanyon C.A., Bernard O., Caroni P. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature. 1998;393:805–809. doi: 10.1038/31729. [DOI] [PubMed] [Google Scholar]
- Arevolo J.C., Pereira D.B., Yano H., Teng K.K., Chao M.V. Identification of a switch in neurotrophin signaling by selective tyrosine phosphorylation. J Biol Chem. 2006;281:1001–1007. doi: 10.1074/jbc.M504163200. [DOI] [PubMed] [Google Scholar]
- Atherton-Fessler S., Hannig G., Piwnica-Worms H. Reversible tyrosine phosphorylation and cell cycle control. Semin Cell Biol. 1993;4:433–442. doi: 10.1006/scel.1993.1051. [DOI] [PubMed] [Google Scholar]
- Atkins C.M., Chen S.J., Klann E., Sweatt J.D. Increased phosphorylation of myelin basic protein during hippocampal long-term potentiation. J Neurochem. 1997;68:1960–1967. doi: 10.1046/j.1471-4159.1997.68051960.x. [DOI] [PubMed] [Google Scholar]
- Aubin J., Davy A., Soriano P. In vivo convergence of BMP and MAPK signaling pathways: impact of differential Smad1 phosphorylation on development and homeostasis. Gene Dev. 2004;18:1482–1494. doi: 10.1101/gad.1202604. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aubol B.E., Ungs L., Lukasiewicz R., Ghosh G., Adams J.A. Chemical clamping allows for efficient phosphorylation of the RNA carrier protein Npl3. J Biol Chem. 2004;279:30182–30188. doi: 10.1074/jbc.M402797200. [DOI] [PubMed] [Google Scholar]
- Ba A.N., Moses A.M. Evolution of characterized phosphorylation sites in budding yeast. Mol Biol Evol. 2010;27:2027–2037. doi: 10.1093/molbev/msq090. [DOI] [PubMed] [Google Scholar]
- Barberis L., Pasquali C., Bertschy-Meier D., Cuccurullo A., Costa C., Ambrogi C., Vilbois F., Chiarle R., Wymann M., Altruda F., et al. Leukocyte transmigration is modulated by chemokine-mediated PI3K gamma-dependent phosphorylation of vimentin. Eur J Immunol. 2009;39:1136–1146. doi: 10.1002/eji.200838884. [DOI] [PubMed] [Google Scholar]
- Barria A., Muller D., Derkach V., Griffith L.C., Soderling T.R. Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. Science. 1997;276:2042–2045. doi: 10.1126/science.276.5321.2042. [DOI] [PubMed] [Google Scholar]
- Bianchini A., Loiarro M., Bielli P., Busa R., Paronetto M.P., Loreni F., Geremia R., Sette C. Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells. Carcinogenesis. 2008;29:2279–2288. doi: 10.1093/carcin/bgn221. [DOI] [PubMed] [Google Scholar]
- Blaydes J.P., Luciani M.G., Pospisilova S., Ball H.M.L., Vojtesek B., Hupp T.R. Stoichiometric phosphorylation of human p53 at Ser(315) stimulates p53-dependent transcription. J Biol Chem. 2001;276:4699–4708. doi: 10.1074/jbc.M003485200. [DOI] [PubMed] [Google Scholar]
- Blom N., Gammeltoft S., Brunak S. Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol. 1999;294:1351–1362. doi: 10.1006/jmbi.1999.3310. [DOI] [PubMed] [Google Scholar]
- Blom N., Sicheritz-Ponten T., Gupta R., Gammeltoft S., Brunak S. Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics. 2004;4:1633–1649. doi: 10.1002/pmic.200300771. [DOI] [PubMed] [Google Scholar]
- Boehm M., Yoshimoto T., Crook M.F., Nallamshetty S., True A., Nabel G.J., Nabel E.G. A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression. EMBO J. 2002;21:3390–3401. doi: 10.1093/emboj/cdf343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bornhauser B.C., Lindholm D. MSAP enhances migration of C6 glioma cells through phosphorylation of the myosin regulatory light chain. Cell Mol Life Sci. 2005;62:1260–1266. doi: 10.1007/s00018-005-5055-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bouzioukh F., Wilkinson G.A., Adelmann G., Frotscher M., Stein V., Klein R. Tyrosine phosphorylation sites in ephrinB2 are required for hippocampal long-term Potentiation but not long-term depression. J Neurosci. 2007;27:11279–11288. doi: 10.1523/JNEUROSCI.3393-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bradbury E.M., Inglis R.J., Matthews H.R. Control of cell-division by very lysine rich histone (F1) phosphorylation. Nature. 1974;247:257–261. doi: 10.1038/247257a0. [DOI] [PubMed] [Google Scholar]
- Brunton V.G., Avizienyte E., Fincham V.J., Serrels B., Metcalf C.A., Sawyer T.K., Frame M.C. Identification of Src-specific phosphorylation site on focal adhesion kinase: Dissection of the role of Src SH2 and catalytic functions and their consequences for tumor cell behavior. Cancer Res. 2005;65:1335–1342. doi: 10.1158/0008-5472.CAN-04-1949. [DOI] [PubMed] [Google Scholar]
- Busino L., Chiesa M., Draetta G.F., Donzelli M. Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene. 2004;23:2050–2056. doi: 10.1038/sj.onc.1207394. [DOI] [PubMed] [Google Scholar]
- Butowt R., von Bartheld C.S. Fates of neurotrophins after retrograde axonal transport: phosphorylation of p75NTR is a sorting signal for delayed degradation. J Neurosci. 2009;29:10715–10729. doi: 10.1523/JNEUROSCI.2512-09.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Caenepeel S., Charydczak G., Sudarsanam S., Hunter T., Manning G. The mouse kinome: Discovery and comparative genomics of all mouse protein kinases. Proc Natl Acad Sci U S A. 2004;101:11707–11712. doi: 10.1073/pnas.0306880101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cai, N., Li, M., Qu, J., Liu, G.H., and Izpisua Belmonte, J.C. (2012). Post-translational modulation of pluripotency. J Mol Cell Biol. (In Press). [DOI] [PubMed]
- Calalb M.B., Polte T.R., Hanks S.K. Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase-activity — a role for src family kinases. Mol Cell Biol. 1995;15:954–963. doi: 10.1128/mcb.15.2.954. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cappuzzo F., Magrini E., Ceresoli G.L., Bartolini S., Rossi E., Ludovini V., Gregorc V., Ligorio C., Cancellieri A., Damiani S., et al. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 2004;96:1133–1141. doi: 10.1093/jnci/djh217. [DOI] [PubMed] [Google Scholar]
- Capron B., Wattiez R., Sindic C., Godaux E., Ris L. Tyrosine phosphorylation of rabphilin during long-lasting long-term potentiation. Neurosci Lett. 2007;414:257–262. doi: 10.1016/j.neulet.2006.12.031. [DOI] [PubMed] [Google Scholar]
- Carriere A., Cargnello M., Julien L.A., Gao H., Bonneil E., Thibault P., Roux P.P. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated Raptor phosphorylation. Curr Biol. 2008;18:1269–1277. doi: 10.1016/j.cub.2008.07.078. [DOI] [PubMed] [Google Scholar]
- Chang N.S., Doherty J., Ensign A., Schultz L., Hsu L.J., Hong Q.Y. WOX1 is essential for tumor necrosis factor-, UV light-, staurosporine-, and p53-mediated cell death, and its tyrosine 33-phosphorylated form binds and stabilizes serine 46-phosphorylated p53. J Biol Chem. 2005;280:43100–43108. doi: 10.1074/jbc.M505590200. [DOI] [PubMed] [Google Scholar]
- Chen H.C., Appeddu P.A., Isoda H., Guan J.L. Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. J Biol Chem. 1996;271:26329–26334. doi: 10.1074/jbc.271.42.26329. [DOI] [PubMed] [Google Scholar]
- Chen S.Y., Xu Y.Y., Yuan X., Bubley G.J., Balk S.P. Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proc Natl Acad Sci U S A. 2006;103:15969–15974. doi: 10.1073/pnas.0604193103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chung S.H. Aberrant phosphorylation in the pathogenesis of Alzheimer’s disease. BMB Rep. 2009;42:467–474. doi: 10.5483/bmbrep.2009.42.8.467. [DOI] [PubMed] [Google Scholar]
- Cicenas J. The potential role of Akt phosphorylation in human cancers. Int J Biol Marker. 2008;23:1–9. doi: 10.1177/172460080802300101. [DOI] [PubMed] [Google Scholar]
- Clayton E.L., Sue N., Smillie K.J., O’Leary T., Bache N., Cheung G., Cole A.R., Wyllie D.J., Sutherland C., Robinson P.J., et al. Dynamin I phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles. Nat Neurosci. 2010;13:845–U885. doi: 10.1038/nn.2571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cohen P. The regulation of protein function by multisite phosphorylation—a 25 year update. Trends Biochem Sci. 2000;25:596–601. doi: 10.1016/s0968-0004(00)01712-6. [DOI] [PubMed] [Google Scholar]
- Collares-Buzato C.B., Jepson M.A., Simmons N.L., Hirst B.H. Increased tyrosine phosphorylation causes redistribution of adherens junction and tight junction proteins and perturbs paracellular barrier function in MDCK epithelia. Eur J Cell Biol. 1998;76:85–92. doi: 10.1016/S0171-9335(98)80020-4. [DOI] [PubMed] [Google Scholar]
- Collawn J.F. Unlocking the mysteries of Na+-K+-ATPase endocytosis — Phosphorylation is the key. Am J Resp Cell Mol. 2006;35:1–2. doi: 10.1165/rcmb.f317. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coluccia A.M.L., Vacca A., Dunach M., Mologni L., Redaelli S., Bustos V.H., Benati D., Pinna L.A., Gambacorti-Passerini C. Bcr-Abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J. 2007;26:1456–1466. doi: 10.1038/sj.emboj.7601485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Consortium U. Reorganizing the protein space at the Universal Protein Resource (UniProt) Nucleic Acids Res. 2012;40:D71–D75. doi: 10.1093/nar/gkr981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Copp J., Manning G., Hunter T. TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res. 2009;69:1821–1827. doi: 10.1158/0008-5472.CAN-08-3014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cousin M.A., Tan T.C., Robinson P.J. Protein phosphorylation is required for endocytosis in nerve terminals: potential role for the dephosphins dynamin I and synaptojanin, but not AP180 or amphiphysin. J Neurochem. 2001;76:105–116. doi: 10.1046/j.1471-4159.2001.00049.x. [DOI] [PubMed] [Google Scholar]
- D’Alessandris C., Lauro R., Presta I., Sesti G. C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser(307) and Ser(612) in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport. Diabetologia. 2007;50:840–849. doi: 10.1007/s00125-006-0522-y. [DOI] [PubMed] [Google Scholar]
- D’Orazi G., Cecchinelli B., Bruno T., Manni I., Higashimoto Y., Saito S., Gostissa M., Coen S., Marchetti A., Del Sal G., et al. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat Cell Biol. 2002;4:11–19. doi: 10.1038/ncb714. [DOI] [PubMed] [Google Scholar]
- Dai N., Rapley J., Angel M., Yanik M.F., Blower M.D., Avruch J. mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry. Gene Dev. 2011;25:1159–1172. doi: 10.1101/gad.2042311. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dekel N. Protein phosphorylation/dephosphorylation in the meiotic cell cycle of mammalian oocytes. Rev Reprod. 1996;1:82–88. doi: 10.1530/ror.0.0010082. [DOI] [PubMed] [Google Scholar]
- Deming D., Geiger P., Chen H., Kunnimalaiyaan M., Holen K. ZM336372 induces apoptosis associated with phosphorylation of GSK-3 beta in pancreatic adenocarcinoma cell lines. J Surg Res. 2010;161:28–32. doi: 10.1016/j.jss.2009.06.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- El Sheikh S.S., Domin J., Abel P., Stamp G., Lalani E.N. Phosphorylation of both EGFR and ErbB2 is a reliable predictor of prostate cancer cell proliferation in response to EGF. Neoplasia. 2004;6:846–853. doi: 10.1593/neo.04379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fan H.Y., Tong C., Chen D.Y., Sun Q.Y. Roles of MAP kinase signaling pathway in oocyte meiosis. Chinese Sci Bull. 2002;47:1157–1162. [Google Scholar]
- Fan Y.X., Wong L.L., Johnson G.R. EGFR kinase possesses a broad specificity for ErbB phosphorylation sites, and ligand increases catalytic-centre activity without affecting substrate binding affinity. Biochem J. 2005;392:417–423. doi: 10.1042/BJ20051122. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Feng H., Hu B., Liu K.W., Li Y., Lu X., Cheng T., Yiin J.J., Lu S., Keezer S., Fenton T., et al. Activation of Rac1 by Src-dependent phosphorylation of Dock180(Y1811) mediates PDGFRalpha-stimulated glioma tumorigenesis in mice and humans. J Clin Invest. 2011;121:4670–4684. doi: 10.1172/JCI58559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fernandez-Borja M., van Buul J.D., Hordijk P.L. The regulation of leucocyte transendothelial migration by endothelial signalling events. Cardiovasc Res. 2010;86:202–210. doi: 10.1093/cvr/cvq003. [DOI] [PubMed] [Google Scholar]
- Ficarro S.B., McCleland M.L., Stukenberg P.T., Burke D.J., Ross M.M., Shabanowitz J., Hunt D.F., White F.M. Phosphoproteome analysis by mass spectrometry and its application to Saccharomyces cerevisiae. Nat Biotechnol. 2002;20:301–305. doi: 10.1038/nbt0302-301. [DOI] [PubMed] [Google Scholar]
- Finn G., Lu K.P. Phosphorylation-specific prolyl isomerase Pin1 as a new diagnostic and therapeutic target for cancer. Curr Cancer Drug Targets. 2008;8:223–229. doi: 10.2174/156800908784293622. [DOI] [PubMed] [Google Scholar]
- Foster J.S., Wimalasena J. Estrogen regulates activity of cyclin-dependent kinases and retinoblastoma protein phosphorylation in breast cancer cells. Mol Endocrinol. 1996;10:488–498. doi: 10.1210/mend.10.5.8732680. [DOI] [PubMed] [Google Scholar]
- Fujii S., Kuroda Y., Ito K., Kato H. Long-term potentiation induction — A synaptic catch mechanism released by extracellular phosphorylation. Neuroscience. 2000;96:259–266. doi: 10.1016/s0306-4522(99)00559-x. [DOI] [PubMed] [Google Scholar]
- Fujita N., Sato S., Katayama K., Tsuruo T. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem. 2002;277:28706–28713. doi: 10.1074/jbc.M203668200. [DOI] [PubMed] [Google Scholar]
- Fujita N., Sato S., Tsuruo T. Phosphorylation of p27(Kip1) at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization. J Biol Chem. 2003;278:49254–49260. doi: 10.1074/jbc.M306614200. [DOI] [PubMed] [Google Scholar]
- Gnad, F., Ren, S.B., Cox, J., Olsen, J.V., Macek, B., Oroshi, M., and Mann, M. (2007). PHOSIDA (phosphorylation site database): management, structural and evolutionary investigation, and prediction of phosphosites. Genome Biol 8. [DOI] [PMC free article] [PubMed]
- Gomez S., Llosas M.D., Verdu J., Roura S., Lloreta J., Fabre M., de Herreros A.G. Independent regulation of adherens and tight junctions by tyrosine phosphorylation in Caco-2 cells. Bba-Mol Cell Res. 1999;1452:121–132. doi: 10.1016/s0167-4889(99)00124-x. [DOI] [PubMed] [Google Scholar]
- Gual P., Le Marchand-Brustel Y., Tanti J.F. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie. 2005;87:99–109. doi: 10.1016/j.biochi.2004.10.019. [DOI] [PubMed] [Google Scholar]
- Haldar S., Chintapalli J., Croce C.M. Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res. 1996;56:1253–1255. [PubMed] [Google Scholar]
- Hao B., Zheng N., Schulman B.A., Wu G., Miller J.J., Pagano M., Pavletich N.P. Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Mol Cell. 2005;20:9–19. doi: 10.1016/j.molcel.2005.09.003. [DOI] [PubMed] [Google Scholar]
- Head J.A., Jiang D.Y., Li M., Zorn L.J., Schaefer E.M., Parsons J.T., Weed S.A. Cortactin tyrosine phosphorylation requires Rac1 activity and association with the cortical actin cytoskeleton. Mol Biol Cell. 2003;14:3216–3229. doi: 10.1091/mbc.E02-11-0753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hirano K., Hirano M., Kanaide H. Regulation of myosin phosphorylation and myofilament Ca2+ sensitivity in vascular smooth muscle. J Smooth Muscle Res. 2004;40:219–236. doi: 10.1540/jsmr.40.219. [DOI] [PubMed] [Google Scholar]
- Hofmann T.G., Moller A., Sirma H., Zentgraf H., Taya Y., Droge W., Will H., Schmitz M.L. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat Cell Biol. 2002;4:1–10. doi: 10.1038/ncb715. [DOI] [PubMed] [Google Scholar]
- Hornbeck P.V., Kornhauser J.M., Tkachev S., Zhang B., Skrzypek E., Murray B., Latham V., Sullivan M. Phospho-SitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res. 2012;40:D261–D270. doi: 10.1093/nar/gkr1122. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iakoucheva L.M., Radivojac P., Brown C.J., O’Connor T.R., Sikes J.G., Obradovic Z., Dunker A.K. The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res. 2004;32:1037–1049. doi: 10.1093/nar/gkh253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Itoh N., Semba S., Ito M., Takeda H., Kawata S., Yamakawa M. Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer. 2002;94:3127–3134. doi: 10.1002/cncr.10591. [DOI] [PubMed] [Google Scholar]
- Jaggi M., Rao P.S., Smith D.J., Wheelock M.J., Johnson K.R., Hernstreet G.P., Balaji K.C. E-cadherin phosphorylation by protein kinase D1 protein kinase C mu is associated with altered cellular aggregation and motility in prostate cancer. Cancer Res. 2005;65:483–492. [PubMed] [Google Scholar]
- Jalkanen S.E., Vakkila J., Kreutzman A., Nieminen J.K., Porkka K., Mustjoki S. Poor cytokine-induced phosphorylation in chronic myeloid leukemia patients at diagnosis is effectively reversed by tyrosine kinase inhibitor therapy. Exp Hematol. 2011;39:102–113. doi: 10.1016/j.exphem.2010.09.005. [DOI] [PubMed] [Google Scholar]
- Jiang C., Hu H.B., Malewicz B., Wang Z.S., Lu J.X. Selenite-induced p53 Ser-15 phosphorylation and caspase-mediated apoptosis in LNCaP human prostate cancer cells. Mol Cancer Ther. 2004;3:877–884. [PubMed] [Google Scholar]
- Jilani I., Kantarjian H., Gorre M., Cortes J., Ottmann O., Bhalla K., Giles F.J., Albitar M. Phosphorylation levels of BCR-ABL, CrkL, AKT and STAT5 in imatinib-resistant chronic myeloid leukemia cells implicate alternative pathway usage as a survival strategy. Leukemia Res. 2008;32:643–649. doi: 10.1016/j.leukres.2007.08.009. [DOI] [PubMed] [Google Scholar]
- Ju J.W., Bandyopadhyay A., Im W.B., Chung J., Kwon H.B., Choi H.S. Involvement of phosphatidylinositol 3 kinase in the progesterone-induced oocyte maturation in Rana dybowskii. Gen Comp Endocr. 2002;126:213–220. doi: 10.1006/gcen.2002.7795. [DOI] [PubMed] [Google Scholar]
- Junttila M.R., Li S.P., Westermarck J. Phosphatase-mediated crosstalk between MAPK signalling pathways in the regulation of cell survival. Faseb J. 2008;22:954–965. doi: 10.1096/fj.06-7859rev. [DOI] [PubMed] [Google Scholar]
- Kanamori Y., Kigawa J., Itamochi H., Shimada M., Takahashi M., Kamazawa S., Sato S., Akeshima R., Terakawa N. Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma. Clin Cancer Res. 2001;7:892–895. [PubMed] [Google Scholar]
- Kapoor M., Hamm R., Yan W., Taya Y., Lozano G. Cooperative phosphorylation at multiple sites is required to activate p53 in response to UV radiation. Oncogene. 2000;19:358–364. doi: 10.1038/sj.onc.1203300. [DOI] [PubMed] [Google Scholar]
- Karin M., Ben-Neriah Y. Phosphorylation meets ubiquitination: The control of NF-kappa B activity. Annu Rev Immunol. 2000;18:621–663. doi: 10.1146/annurev.immunol.18.1.621. [DOI] [PubMed] [Google Scholar]
- Khadjavi A., Barbero G., Destefanis P., Mandili G., Giribaldi G., Mannu F., Pantaleo A., Ceruti C., Bosio A., Rolle L., et al. Evidence of Abnormal Tyrosine Phosphorylated Proteins in the Urine of Patients With Bladder Cancer: The Road Toward a New Diagnostic Tool? J Urology. 2011;185:1922–1929. doi: 10.1016/j.juro.2010.12.029. [DOI] [PubMed] [Google Scholar]
- Kim S.J., Rabbani Z.N., Vollmer R.T., Schreiber E.G., Dewhirst M.W., Vujaskovic Z., Kelley M.J. Expression of phosphorylated epidermal growth factor receptor (p-EGFR) in early stage non-small cell lung cancer: its relationship with overexpression of EGFR and cyclooxygenase-2 (COX-2), and survival. J Clin Oncol. 2005;23:864s–864s. [Google Scholar]
- Kim, Y., Paroush, Z., Nairz, K., Hafen, E., Jimenez, G., and Shvartsman, S.Y. (2011). Substrate-dependent control of MAPK phosphorylation in vivo. Mol Syst Biol 7. [DOI] [PMC free article] [PubMed]
- Kleinman D., Karas M., Danilenko M., Arbeli A., Roberts C.T., LeRoith D., Levy J., Sharoni Y. Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased insulin-like growth factor (IGF)-I induced tyrosine phosphorylation and reduction in IGF binding proteins. Endocrinology. 1996;137:1089–1095. doi: 10.1210/endo.137.3.8603578. [DOI] [PubMed] [Google Scholar]
- Koepp D.M., Schaefer L.K., Ye X., Keyomarsi K., Chu C., Harper J.W., Elledge S.J. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science. 2001;294:173–177. doi: 10.1126/science.1065203. [DOI] [PubMed] [Google Scholar]
- Konishi Y., Lehtinen M., Donovan N., Bonni A. Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Mol Cell. 2002;9:1005–1016. doi: 10.1016/s1097-2765(02)00524-5. [DOI] [PubMed] [Google Scholar]
- Kordowska J., Huang R.J., Wang C.L.A. Phosphorylation of caldesmon during smooth muscle contraction and cell migration or proliferation. J Biomed Sci. 2006;13:159–172. doi: 10.1007/s11373-005-9060-8. [DOI] [PubMed] [Google Scholar]
- Kornberg L., Earp H.S., Parsons J.T., Schaller M., Juliano R.L. Cell-adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine kinase. J Biol Chem. 1992;267:23439–23442. [PubMed] [Google Scholar]
- Kreisberg J.I., Malik S.N., Prihoda T.J., Bedolla R.G., Troyer D.A., Kreisberg S., Ghosh P.M. Phosphorylation of Akt (Ser(473)) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res. 2004;64:5232–5236. doi: 10.1158/0008-5472.CAN-04-0272. [DOI] [PubMed] [Google Scholar]
- Kruck S., Bedke J., Hennenlotter J., Ohneseit P.A., Kuehs U., Senger E., Sievert K.D., Stenzl A. Activation of mTOR in renal cell carcinoma is due to increased phosphorylation rather than protein overexpression. Oncol Rep. 2010;23:159–163. [PubMed] [Google Scholar]
- Landry C.R., Levy E.D., Michnick S.W. Weak functional constraints on phosphoproteomes. Trends Genet. 2009;25:193–197. doi: 10.1016/j.tig.2009.03.003. [DOI] [PubMed] [Google Scholar]
- Lee E.W., Lee M.S., Camus S., Ghim J., Yang M.R., Oh W., Ha N.C., Lane D.P., Song J. Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis. EMBO J. 2009;28:2100–2113. doi: 10.1038/emboj.2009.164. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee M.G., Norbury C.J., Spurr N.K., Nurse P. Regulated expression and phosphorylation of a possible mammalian cell-cycle control protein. Nature. 1988;333:676–679. doi: 10.1038/333676a0. [DOI] [PubMed] [Google Scholar]
- Lee S.H., Kim H.S., Park W.S., Kim S.Y., Lee K.Y., Kim S.H., Lee J.Y., Yoo N.J. Non-small cell lung cancers frequently express phosphorylated Akt; an immunohistochemical study. APMIS. 2002;110:587–592. doi: 10.1034/j.1600-0463.2002.11007811.x. [DOI] [PubMed] [Google Scholar]
- Lew D.J., Kornbluth S. Regulatory roles of cyclin dependent kinase phosphorylation in cell cycle control. Curr Opin Cell Biol. 1996;8:795–804. doi: 10.1016/s0955-0674(96)80080-9. [DOI] [PubMed] [Google Scholar]
- Li Z.L., Li J.F., Bu X.N., Liu X., Tankersley C.G., Wang C., Huang K.W. Age-induced augmentation of p38 MAPK phosphorylation in mouse lung. Exp Gerontol. 2011;46:694–702. doi: 10.1016/j.exger.2011.04.005. [DOI] [PubMed] [Google Scholar]
- Liang C.G., Su Y.Q., Fan H.Y., Schatten H., Sun Q.Y. Mechanisms regulating oocyte meiotic resumption: roles of mitogen-activated protein kinase. Mol Endocrinol. 2007;21:2037–2055. doi: 10.1210/me.2006-0408. [DOI] [PubMed] [Google Scholar]
- Lin H.Y., Shih A., Davis F.B., Tang H.Y., Martino L.J., Bennett J.A., Davis P.J. Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line. J Urology. 2002;168:748–755. [PubMed] [Google Scholar]
- Lonart G., Schoch S., Kaeser P.S., Larkin C.J., Sudhof T.C., Linden D.J. Phosphorylation of RIM1 alpha by PKA triggers presynaptic long-term potentiation at cerebellar parallel fiber synapses. Cell. 2003;115:49–60. doi: 10.1016/s0092-8674(03)00727-x. [DOI] [PubMed] [Google Scholar]
- Ma D.J., Wang J.R., Zhao Y.C., Lee W.N.P., Xiao J., Go V.L.W., Wang Q., Recker R.R., Xiao G.G. Inhibition of glycogen phosphorylation induces changes in cellular proteome and signaling pathways in MIA pancreatic cancer cells. Pancreas. 2012;41:397–408. doi: 10.1097/MPA.0b013e318236f022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mahajan N.P., Liu Y., Majumder S., Warren M.R., Parker C.E., Mohler J.L., Earp H.S., Whang Y.E. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci U S A. 2007;104:8438–8443. doi: 10.1073/pnas.0700420104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Manabe T., Aiba A., Yamada A., Ichise T., Sakagami H., Kondo H., Katsuki M. Regulation of long-term potentiation by H-Ras through NMDA receptor phosphorylation. J Neurosci. 2000;20:2504–2511. doi: 10.1523/JNEUROSCI.20-07-02504.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Manning G., Plowman G.D., Hunter T., Sudarsanam S. Evolution of protein kinase signaling from yeast to man. Trends Biochem Sci. 2002;27:514–520. doi: 10.1016/s0968-0004(02)02179-5. [DOI] [PubMed] [Google Scholar]
- Manning G., Whyte D.B., Martinez R., Hunter T., Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912–1934. doi: 10.1126/science.1075762. [DOI] [PubMed] [Google Scholar]
- Mathew R., Hartmuth K., Mohlmann S., Urlaub H., Ficner R., Luhrmann R. Phosphorylation of human PRP28 by SRPK2 is required for integration of the U4/U6-U5 tri-snRNP into the spliceosome. Nat Struct Mol Biol. 2008;15:435–443. doi: 10.1038/nsmb.1415. [DOI] [PubMed] [Google Scholar]
- Matsumoto H., Sakamoto A., Fujiwara M., Yano Y., Shishido-Hara Y., Fujioka Y., Kamma H. Cyclic AMP-mediated growth suppression and MAPK phosphorylation in thyroid papillary carcinoma cells. Mol Med Rep. 2008;1:245–249. [PubMed] [Google Scholar]
- Matsuoka S., Huang M.X., Elledge S.J. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 1998;282:1893–1897. doi: 10.1126/science.282.5395.1893. [DOI] [PubMed] [Google Scholar]
- Mayrose I., Graur D., Ben-Tal N., Pupko T. Comparison of site-specific rate-inference methods for protein sequences: empirical Bayesian methods are superior. Mol Biol Evol. 2004;21:1781–1791. doi: 10.1093/molbev/msh194. [DOI] [PubMed] [Google Scholar]
- McDonough W.S., Tran N.L., Berens M.E. Regulation of glioma cell migration by serine-phosphorylated P311. Neoplasia. 2005;7:862–872. doi: 10.1593/neo.05190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McManus E.J., Sakamoto K., Armit L.J., Ronaldson L., Shpiro N., Marquez R., Alessi D.R. Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J. 2005;24:1571–1583. doi: 10.1038/sj.emboj.7600633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mermoud J.E., Cohen P.T.W., Lamond A.I. Regulation of mammalian spliceosome assembly by a protein-phosphorylation mechanism. EMBO J. 1994;13:5679–5688. doi: 10.1002/j.1460-2075.1994.tb06906.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mimura Y., Ihn H., Jinnin M., Asano Y., Yamane K., Tamaki K. Constitutive phosphorylation of focal adhesion kinase is involved in the myofibroblast differentiation of scleroderma fibroblasts. J Invest Dermatol. 2005;124:886–892. doi: 10.1111/j.0022-202X.2005.23701.x. [DOI] [PubMed] [Google Scholar]
- Miyata Y., Sagara Y., Kanda S., Hayashi T., Kanetake H. Phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor growth and prognosis in patients with bladder cancer: correlation with matrix metalloproteinase-2 and-7 and E-cadherin. Hum Pathol. 2009;40:496–504. doi: 10.1016/j.humpath.2008.09.011. [DOI] [PubMed] [Google Scholar]
- Morrison D.K., Murakami M.S., Cleghon V. Protein kinases and phosphatases in the Drosophila genome. J Cell Biol. 2000;150:F57–F62. doi: 10.1083/jcb.150.2.f57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Motti M.L., De Marco C., Califano D., Fusco A., Viglietto G. Akt-dependent T198 phosphorylation of cyclin-dependent kinase inhibitor p27kip1 in breast cancer. Cell Cycle. 2004;3:1074–1080. [PubMed] [Google Scholar]
- Muller W.A. Mechanisms of transendothelial migration of leukocytes. Circ Res. 2009;105:223–230. doi: 10.1161/CIRCRESAHA.109.200717. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mulner O., Megret F., Alouf J.E., Ozon R. Pertussis toxin facilitates the progesterone-induced maturation of Xenopus oocyte. Possible role of protein phosphorylation. FEBS Lett. 1985;181:397–402. doi: 10.1016/0014-5793(85)80300-8. [DOI] [PubMed] [Google Scholar]
- Muslin A.J., Macnicol A.M., Williams L.T. Raf-1 proteinkinase is important for progesterone-induced xenopus-oocyte maturation and acts downstream of Mos. Mol Cell Biol. 1993;13:4197–4202. doi: 10.1128/mcb.13.7.4197. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mutoh T., Sobue G., Hamano T., Kuriyama M., Hirayama M., Yamamoto M., Mitsuma T. Decreased phosphorylation levels of TrkB neurotrophin receptor in the spinal cords from patients with amyotrophic lateral sclerosis. Neurochem Res. 2000;25:239–245. doi: 10.1023/a:1007575504321. [DOI] [PubMed] [Google Scholar]
- Myers M.G., Mendez R., Shi P., Pierce J.H., Rhoads R., White M.F. The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling. J Biol Chem. 1998;273:26908–26914. doi: 10.1074/jbc.273.41.26908. [DOI] [PubMed] [Google Scholar]
- Mylonis I., Chachami G., Samiotaki M., Panayotou G., Paraskeva E., Kalousi A., Georgatsou E., Bonanou S., Simos G. Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1 alpha. J Biol Chem. 2006;281:33095–33106. doi: 10.1074/jbc.M605058200. [DOI] [PubMed] [Google Scholar]
- Nakada M., Anderson E.M., Demuth T., Nakada S., Reavie L.B., Drake K.L., Hoelzinger D.B., Berens M.E. The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion. Int J Cancer. 2010;126:1155–1165. doi: 10.1002/ijc.24849. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakada M., Niska J.A., Miyamori H., McDonough W.S., Wu J., Sato H., Berens M.E. The phosphorylation of EphB2 receptor regulates migration and invasion of human glioma cells. Cancer Res. 2004;64:3179–3185. doi: 10.1158/0008-5472.can-03-3667. [DOI] [PubMed] [Google Scholar]
- Nakashima M., Adachi S., Yasuda I., Yamauchi T., Kawaguchi J., Itani M., Yoshioka T., Matsushima-Nishiwaki R., Hirose Y., Kozawa O., et al. Phosphorylation status of heat shock protein 27 plays a key role in gemcitabine-induced apoptosis of pancreatic cancer cells. Cancer Lett. 2011;313:218–225. doi: 10.1016/j.canlet.2011.09.008. [DOI] [PubMed] [Google Scholar]
- Nebreda A.R., Gannon J.V., Hunt T. Newly synthesized protein(s) must associate with P34(Cdc2) to activate Map kinase and Mpf during progesterone-induced maturation of Xenopus oocytes. EMBO J. 1995;14:5597–5607. doi: 10.1002/j.1460-2075.1995.tb00247.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ng S.S.W., Tsao M.S., Nicklee T., Hedley D.W. Wortmannin inhibits PKB/Akt phosphorylation and promotes gemeitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin Cancer Res. 2001;7:3269–3275. [PubMed] [Google Scholar]
- Nigam S.K., Denisenko N., Rodriguezboulan E., Citi S. The role of phosphorylation in development of tight junctions in cultured renal epithelial (Mdck) cells. Biochem Bioph Res Co. 1991;181:548–553. doi: 10.1016/0006-291x(91)91224-z. [DOI] [PubMed] [Google Scholar]
- Nucifora P.G.P., Fox A.P. Tyrosine phosphorylation regulates rapid endocytosis in adrenal chromaffin cells. J Neurosci. 1999;19:9739–9746. doi: 10.1523/JNEUROSCI.19-22-09739.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oda A., Miyakawa Y., Druker B.J., Ishida A., Ozaki K., Ohashi H., Wakui M., Handa M., Watanabe K., Okamoto S., et al. Crkl is constitutively tyrosine phosphorylated in platelets from chronic myelogenous leukemia patients and inducibly phosphorylated in normal platelets stimulated by thrombopoietin. Blood. 1996;88:4304–4313. [PubMed] [Google Scholar]
- Ollila S., Makela T.P. The tumor suppressor kinase LKB1: lessons from mouse models. J Mol Cell Biol. 2011;3:330–340. doi: 10.1093/jmcb/mjr016. [DOI] [PubMed] [Google Scholar]
- Ou T.T., Wu C.H., Hsu J.D., Chyau C.C., Lee H.J., Wang C.J. Paeonia lactiflora Pall inhibits bladder cancer growth involving phosphorylation of Chk2 in vitro and in vivo. J Ethnopharmacol. 2011;135:162–172. doi: 10.1016/j.jep.2011.03.011. [DOI] [PubMed] [Google Scholar]
- Oude Weernink P.A., Verheul E., Kerkhof E., van Veelen C.W., Rijksen G. Inhibitors of protein tyrosine phosphorylation reduce the proliferation of two human glioma cell lines. Neurosurgery. 1996;38:108–113. doi: 10.1097/00006123-199601000-00026. [DOI] [PubMed] [Google Scholar]
- Park J., Sung J.Y., Park J., Song W.J., Chang S., Chung K.C. Dyrk1A negatively regulates the actin cytoskeleton through threonine phosphorylation of N-WASP. J Cell Sci. 2012;125:67–80. doi: 10.1242/jcs.086124. [DOI] [PubMed] [Google Scholar]
- Pinna L.A., Ruzzene M. How do protein kinases recognize their substrates? Biochim Biophys Acta. 1996;1314:191–225. doi: 10.1016/s0167-4889(96)00083-3. [DOI] [PubMed] [Google Scholar]
- Pupko T., Bell R.E., Mayrose I., Glaser F., Ben-Tal N. Rate4Site: an algorithmic tool for the identification of functional regions in proteins by surface mapping of evolutionary determinants within their homologues. Bioinformatics. 2002;18(Suppl1):S71–77. doi: 10.1093/bioinformatics/18.suppl_1.s71. [DOI] [PubMed] [Google Scholar]
- Rao R. Occludin phosphorylation in regulation of epithelial tight junctions. Ann N Y Acad Sci. 2009;1165:62–68. doi: 10.1111/j.1749-6632.2009.04054.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rosner M., Siegel N., Valli A., Fuchs C., Hengstschlager M. mTOR phosphorylated at S2448 binds to raptor and rictor. Amino Acids. 2010;38:223–228. doi: 10.1007/s00726-008-0230-7. [DOI] [PubMed] [Google Scholar]
- Sabile A., Meyer A.M., Wirbelauer C., Hess D., Kogel U., Scheffner M., Krek W. Regulation of p27 degradation and S-phase progression by Ro52 RING finger protein. Mol Cell Biol. 2006;26:5994–6004. doi: 10.1128/MCB.01630-05. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sakaguchi K., Sakamoto H., Lewis M.S., Anderson C.W., Erickson J.W., Appella E., Xie D. Phosphorylation of serine 392 stabilizes the tetramer formation of tumor suppressor protein p53. Biochemistry-Us. 1997;36:10117–10124. doi: 10.1021/bi970759w. [DOI] [PubMed] [Google Scholar]
- Sallee J.L., Burridge K. Density-enhanced phosphatase 1 regulates phosphorylation of tight junction proteins and enhances barrier function of epithelial cells. J Biol Chem. 2009;284:14997–15006. doi: 10.1074/jbc.M901901200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sayers E.W., Barrett T., Benson D.A., Bolton E., Bryant S.H., Canese K., Chetvernin V., Church D.M., DiCuccio M., Federhen S., et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 2012;40:D13–D25. doi: 10.1093/nar/gkr1184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schaefer A.W., Kamei Y., Kamiguchi H., Wong E.V., Rapoport I., Kirchhausen T., Beach C.M., Landreth G., Lemmon S.K., Lemmon V. L1 endocytosis is controlled by a phosphorylation-dephosphorylation cycle stimulated by outside-in signaling by L1. J Cell Biol. 2002;157:1223–1232. doi: 10.1083/jcb.200203024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schafe G.E., Swank M.W., Rodrigues S.M., Debiec J., Doyere V. Phosphorylation of ERK/MAP kinase is required for long-term potentiation in anatomically restricted regions of the lateral amygdala in vivo. Learn Memory. 2008;15:55–62. doi: 10.1101/lm.746808. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schmidt N., Akaaboune M., Gajendran N., Martinez-Pena y Valenzuela I., Wakefield S., Thurnheer R., Brenner H.R. Neuregulin/ErbB regulate neuromuscular junction development by phosphorylation of alpha-dystrobrevin. J Cell Biol. 2011;195:1171–1184. doi: 10.1083/jcb.201107083. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Serrano P., Yao Y., Sacktor T.C. Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation. J Neurosci. 2005;25:1979–1984. doi: 10.1523/JNEUROSCI.5132-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Serres M., Filhol O., Lickert H., Grangeasse C., Chambaz E.M., Stappert J., Vincent C., Schmitt D. The disruption of adherens junctions is associated with a decrease of E-cadherin phosphorylation by protein kinase CK2. Exp Cell Res. 2000;257:255–264. doi: 10.1006/excr.2000.4895. [DOI] [PubMed] [Google Scholar]
- Shasby D.M., Ries D.R., Shasby S.S., Winter M.C. Histamine stimulates phosphorylation of adherens junction proteins and alters their link to vimentin. Am J Physiol-Lung C. 2002;282:L1330–L1338. doi: 10.1152/ajplung.00329.2001. [DOI] [PubMed] [Google Scholar]
- Shen L., Black E.D., Witkowski E.D., Lencer W.I., Guerriero V., Schneeberger E.E., Turner J.R. Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure. J Cell Sci. 2006;119:2095–2106. doi: 10.1242/jcs.02915. [DOI] [PubMed] [Google Scholar]
- Shimada K., Nakamura M., Ishida E., Konishi N. Molecular roles of MAP kinases and FADD phosphorylation in prostate cancer. Histol Histopathol. 2006;21:415–422. doi: 10.14670/HH-21.415. [DOI] [PubMed] [Google Scholar]
- Shouse G.P., Cai X., Liu X. Serine 15 phosphorylation of p53 directs its interaction with B56gamma and the tumor suppressor activity of B56gamma-specific protein phosphatase 2A. Mol Cell Biol. 2008;28:448–456. doi: 10.1128/MCB.00983-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Skowyra D., Craig K.L., Tyers M., Elledge S.J., Harper J.W. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell. 1997;91:209–219. doi: 10.1016/s0092-8674(00)80403-1. [DOI] [PubMed] [Google Scholar]
- Slack B.E. Tyrosine phosphorylation of paxillin and focal adhesion kinase by activation of muscarinic m3 receptors is dependent on integrin engagement by the extracellular matrix. Proc Natl Acad Sci U S A. 1998;95:7281–7286. doi: 10.1073/pnas.95.13.7281. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Slepnev V.I., Ochoa G.C., Butler M.H., Grabs D., De Camilli P. Role of phosphorylation in regulation of the assembly of endocytic coat complexes. Science. 1998;281:821–824. doi: 10.1126/science.281.5378.821. [DOI] [PubMed] [Google Scholar]
- Soubeyrand S., Schild-Poulter C., Hache R.J.G. Structured DNA promotes phosphorylation of p53 by DNA-dependent protein kinase at serine 9 and threonine 18. Eur J Biochem. 2004;271:3776–3784. doi: 10.1111/j.1432-1033.2004.04319.x. [DOI] [PubMed] [Google Scholar]
- Sumi T., Matsumoto K., Takai Y., Nakamura T. Cofilin phosphorylation and actin cytoskeletal dynamics regulated by Rho- and Cdc42-activated LIM-kinase 2. J Cell Biol. 1999;147:1519–1532. doi: 10.1083/jcb.147.7.1519. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Swain J.E., Smith G.D. Reversible phosphorylation and regulation of mammalian oocyte meiotic chromatin remodeling and segregation. Soc Reprod Fertil Suppl. 2007;63:343–358. [PubMed] [Google Scholar]
- Sweeney C., Carraway K.L. Ligand discrimination by ErbB receptors: differential signaling through differential phosphorylation site usage. Oncogene. 2000;19:5568–5573. doi: 10.1038/sj.onc.1203913. [DOI] [PubMed] [Google Scholar]
- Szanto A., Bognar Z., Szigeti A., Szabo A., Farkas L., Gallyas F. Critical role of bad phosphorylation by Akt in cytostatic resistance of human bladder cancer cells. Anticancer Res. 2009;29:159–164. [PubMed] [Google Scholar]
- Tang D., Mehta D., Gunst S.J. Mechanosensitive tyrosine phosphorylation of paxillin and focal adhesion kinase in tracheal smooth muscle. Am J Physiol-Cell Ph. 1999;276:C250–C258. doi: 10.1152/ajpcell.1999.276.1.C250. [DOI] [PubMed] [Google Scholar]
- Tang J.M., He Q.Y., Guo R.X., Chang X.J. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer. 2006;51:181–191. doi: 10.1016/j.lungcan.2005.10.003. [DOI] [PubMed] [Google Scholar]
- Tanti J.F., Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol. 2009;9:753–762. doi: 10.1016/j.coph.2009.07.004. [DOI] [PubMed] [Google Scholar]
- Terakawa N., Kanamori Y., Yoshida S. Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer. Endocr-Relat Cancer. 2003;10:203–208. doi: 10.1677/erc.0.0100203. [DOI] [PubMed] [Google Scholar]
- Tinsley J.H., Wu M.H., Ma W.Y., Taulman A.C., Yuan S.Y. Activated neutrophils induce hyperpermeability and phosphorylation of adherens junction proteins in coronary venular endothelial cells. J Biol Chem. 1999;274:24930–24934. doi: 10.1074/jbc.274.35.24930. [DOI] [PubMed] [Google Scholar]
- Topisirovic I., Ruiz-Gutierrez M., Borden K.L.B. Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities. Cancer Res. 2004;64:8639–8642. doi: 10.1158/0008-5472.CAN-04-2677. [DOI] [PubMed] [Google Scholar]
- Tsurutani J., Fukuoka J., Tsurutani H., Shih J.H., Hewitt S.M., Travis W.D., Jen J., Dennis P.A. Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors. J Clin Oncol. 2006;24:306–314. doi: 10.1200/JCO.2005.02.4133. [DOI] [PubMed] [Google Scholar]
- Ubersax J.A., Ferrell J.E., Jr. Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol. 2007;8:530–541. doi: 10.1038/nrm2203. [DOI] [PubMed] [Google Scholar]
- Ueki K., Kondo T., Kahn C.R. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol. 2004;24:5434–5446. doi: 10.1128/MCB.24.12.5434-5446.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ueno M., Carvalheira J.B.C., Tambascia R.C., Bezerra R.M.N., Amaral M.E., Carneiro E.M., Folli F., Franchini K.G., Saad M.J.A. Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Diabetologia. 2005;48:506–518. doi: 10.1007/s00125-004-1662-6. [DOI] [PubMed] [Google Scholar]
- van der Horst E.H., Weber I., Ullrich A. Tyrosine phosphorylation of PYK2 mediates heregulin-induced glioma invasion: Novel heregulin/HER3-stimulated signaling pathway in glioma. International Journal of Cancer. 2005;113:689–698. doi: 10.1002/ijc.20643. [DOI] [PubMed] [Google Scholar]
- Vardouli L., Moustakas A., Stournaras C. LIM-kinase 2 and cofilin phosphorylation mediate actin cytoskeleton reorganization induced by transforming growth factor-beta. J Biol Chem. 2005;280:11448–11457. doi: 10.1074/jbc.M402651200. [DOI] [PubMed] [Google Scholar]
- Viatour P., Merville M.P., Bours V., Chariot A. Phosphorylation of NF-kappa B and I kappa B proteins: implications in cancer and inflammation. Trends Biochem Sci. 2005;30:43–52. doi: 10.1016/j.tibs.2004.11.009. [DOI] [PubMed] [Google Scholar]
- Viegi A., Cotrufo T., Berardi N., Mascia L., Maffei L. Effects of dark rearing on phosphorylation of neurotrophin Trk receptors. Eur J Neurosci. 2002;16:1925–1930. doi: 10.1046/j.1460-9568.2002.02270.x. [DOI] [PubMed] [Google Scholar]
- Viglietto G., Motti M.L., Bruni P., Melillo R.M., D’Alessio A., Califano D., Vinci F., Chiappetta G., Tsichlis P., Bellacosa A., et al. Cytoplasmic relocalization and inhibition of the cyclindependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med. 2002;8:1136–1144. doi: 10.1038/nm762. [DOI] [PubMed] [Google Scholar]
- Vivanco I., Sawyers C.L. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501. doi: 10.1038/nrc839. [DOI] [PubMed] [Google Scholar]
- Vo K., Amarasinghe B., Washington K., Gonzalez A., Berlin J., Dang T.P. Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation. Mol Cancer. 2011;10:138. doi: 10.1186/1476-4598-10-138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Volberg T., Zick Y., Dror R., Sabanay I., Gilon C., Levitzki A., Geiger B. The effect of tyrosine-specific protein-phosphorylation on the assembly of adherens-type junctions. EMBO J. 1992;11:1733–1742. doi: 10.1002/j.1460-2075.1992.tb05225.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Walker J.S., Wingard C.J., Murphy R.A. Energetics of crossbridge phosphorylation and contraction in vascular smooth-muscle. Hypertension. 1994;23:1106–1112. doi: 10.1161/01.hyp.23.6.1106. [DOI] [PubMed] [Google Scholar]
- Wang C.H., Mao X.M., Wang L.X., Liu M.L., Wetzel M.D., Guan K.L., Dong L.Q., Liu F. Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. J Biol Chem. 2007;282:7991–7996. doi: 10.1074/jbc.M700098200. [DOI] [PubMed] [Google Scholar]
- Wang H., Owens C., Chandra N., Conaway M.R., Brautigan D.L., Theodorescu D. Phosphorylation of RalB is important for bladder cancer cell growth and metastasis. Cancer Res. 2010;70:8760–8769. doi: 10.1158/0008-5472.CAN-10-0952. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang J.J.L., Tasinato A., Ethell D.W., Testa M.P., Bredesen D.E. Phosphorylation of the common neurotrophin receptor p75 by p38 beta 2 kinase affects NF-kappa B and AP-1 activities. J Mol Neurosci. 2000;15:19–29. doi: 10.1385/JMN:15:1:19. [DOI] [PubMed] [Google Scholar]
- Wang Q., Wang C.M., Ai J.S., Xiong B., Yin S., Hou Y., Chen D.Y., Schatten H., Sun Q.Y. Histone phosphorylation and pericentromeric histone modifications in oocyte meiosis. Cell Cycle. 2006;5:1974–1982. doi: 10.4161/cc.5.17.3183. [DOI] [PubMed] [Google Scholar]
- Wang X., Bruderer S., Rafi Z., Xue J., Milburn P.J., Kramer A., Robinson P.J. Phosphorylation of splicing factor SF1 on Ser20 by cGMP-dependent protein kinase regulates spliceosome assembly. EMBO J. 1999;18:4549–4559. doi: 10.1093/emboj/18.16.4549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang Y.G., Du D., Fang L.H., Yang G., Zhang C.Y., Zeng R., Ullrich A., Lottspeich F., Chen Z.J. Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling. EMBO J. 2006;25:5058–5070. doi: 10.1038/sj.emboj.7601384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Whistler J.L., Tsao P., von Zastrow M. A phosphorylation-regulated brake mechanism controls the initial endocytosis of opioid receptors but is not required for post-endocytic sorting to lysosomes. J Biol Chem. 2001;276:34331–34338. doi: 10.1074/jbc.M104627200. [DOI] [PubMed] [Google Scholar]
- Willems A.R., Goh T., Taylor L., Chernushevich I., Shevchenko A., Tyers M. SCF ubiquitin protein ligases and phosphorylation-dependent proteolysis. Philos T Roy Soc B. 1999;354:1533–1550. doi: 10.1098/rstb.1999.0497. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Willems A.R., Lanker S., Patton E.E., Craig K.L., Nason T.F., Mathias N., Kobayashi R., Wittenberg C., Tyers M. Cdc53 targets phosphorylated G1 cyclins for degradation by the ubiquitin proteolytic pathway. Cell. 1996;86:453–463. doi: 10.1016/s0092-8674(00)80118-x. [DOI] [PubMed] [Google Scholar]
- Wong Y.H., Lee T.Y., Liang H.K., Huang C.M., Wang T.Y., Yang Y.H., Chu C.H., Huang H.D., Ko M.T., Hwang J.K. KinasePhos 2.0: a web server for identifying protein kinase-specific phosphorylation sites based on sequences and coupling patterns. Nucleic Acids Res. 2007;35:W588–594. doi: 10.1093/nar/gkm322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Xue Y., Li A., Wang L.R., Feng H.Q., Yao X.B. PPSP: prediction of PK-specific phosphorylation site with Bayesian decision theory. BMC Bioinformatics. 2006;7:163. doi: 10.1186/1471-2105-7-163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Xue Y., Liu Z., Cao J., Ma Q., Gao X., Wang Q., Jin C., Zhou Y., Wen L., Ren J. GPS 2.1: enhanced prediction of kinase-specific phosphorylation sites with an algorithm of motif length selection. Protein Eng Des Sel. 2011;24:255–60. doi: 10.1093/protein/gzq094. [DOI] [PubMed] [Google Scholar]
- Yamamoto N., Mammadova G., Song R.X.D., Fukami Y., Sato K. Tyrosine phosphorylation of p145(met) mediated by EGFR and Src is required for serum-independent survival of human bladder carcinoma cells. J Cell Sci. 2006;119:4623–4633. doi: 10.1242/jcs.03236. [DOI] [PubMed] [Google Scholar]
- Yu X.C., Chen J.J. DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains. Mol Cell Biol. 2004;24:9478–9486. doi: 10.1128/MCB.24.21.9478-9486.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zannini, L., Buscemi, G., Kim, J.E., Fontanella, E., and Delia, D. (2012). DBC1 phosphorylation by ATM/ATR inhibits SIRT1 deacetylase in response to DNA damage. J Mol Cell Biol. (In Press). [DOI] [PubMed]
- Zhang T., Mi Z.P., Schor N.F. Role of tyrosine phosphorylation in the antioxidant effects of the p75 neurotrophin receptor. Oxid Med Cell Longev. 2009;2:238–246. doi: 10.4161/oxim.2.4.9745. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang Y.J., Lu C.R., Cao Y., Luo Y., Bao R.F., Yan S., Xue M., Zhu F., Wang Z., Duan L.N. Imatinib induces H2AX phosphorylation and apoptosis in chronic myelogenous leukemia cells in vitro via caspase-3/Mst1 pathway. Acta Pharmacol Sin. 2012;33:551–557. doi: 10.1038/aps.2012.9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang Y.W., Moreland S., Moreland R.S. Regulation of vascular smooth-muscle contraction-myosin light-chain phosphorylation-dependent and independent pathways. Can J Physiol Pharm. 1994;72:1386–1391. doi: 10.1139/y94-200. [DOI] [PubMed] [Google Scholar]
- Zheng L., Foley K., Huang L.Q., Leubner A., Mo G.L., Olino K., Edil B.H., Mizuma M., Sharma R., Le D.T., et al. Tyrosine 23 phosphorylation-dependent cell-surface localization of annexin A2 is required for invasion and metastases of pancreatic cancer. Plos One. 2011;6:e19390. doi: 10.1371/journal.pone.0019390. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhou Y.F., Jiang H., Tang J.G., Tang B.S. [The advances in research on phosphorylation of polyglutamine disease] Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2008;25:414–417. [PubMed] [Google Scholar]
- Zhu J.W., Yu D., Zeng X.C., Zhou K., Zhan X. Receptor-mediated endocytosis involves tyrosine phosphorylation of cortactin. J Biol Chem. 2007;282:16086–16094. doi: 10.1074/jbc.M701997200. [DOI] [PubMed] [Google Scholar]
- Zick Y. Insulin resistance: a phosphorylation-based uncoupling of insulin signaling. Trends Cell Biol. 2001;11:437–441. doi: 10.1016/s0962-8924(01)02129-8. [DOI] [PubMed] [Google Scholar]
- Zolnierowicz S., Bollen M. Protein phosphorylation and protein phosphatases. De Panne, Belgium, September 19–24, 1999. EMBO J. 2000;19:483–488. doi: 10.1093/emboj/19.4.483. [DOI] [PMC free article] [PubMed] [Google Scholar]