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Focal adhesion kinase (FAK) is a protein tyrosine kinase enriched in focal adhesions, which plays a critical role in integrin-dependent cell motility and survival. The crucial step in its activation is autophosphorylation on Tyr-397, which promotes the recruitment of several enzymes including Src family kinases and the activation of multiple signaling pathways. We found in a yeast two-hybrid screen that the N-terminal domain of FAK interacted with protein inhibitor of activated STAT1 (PIAS1). This interaction was confirmed and shown to be direct using in vitro assays. PIAS1 was co-immunoprecipitated with FAK from transfected cells and brain extracts. PIAS1 has recently been recognized as a small ubiquitin-like modifier (SUMO) ligase. In the presence of PIAS1 and SUMO-1, FAK was sumoylated in intact cells, whereas PYK2, a closely related enzyme, was not. Sumoylation occurred on Lys-152, a residue conserved in FAK during evolution. Sumoylated FAK, like PIAS1, was recovered predominantly from the nuclear fraction. Sumoylation did not require the catalytic activity or autophosphorylation of FAK. In contrast, sumoylation increased dramatically the ability of FAK to autophosphorylate in intact cells and in immune precipitate kinase assays. Endogenous FAK was sumoylated in the presence of PIAS1 and SUMO-1 independently of cell adhesion, and autophosphorylation of sumoylated FAK was persistently increased in suspended cells. These observations show that sumoylation controls the activity of a protein kinase and suggest that FAK may play a novel role in signaling between the plasma membrane and the nucleus. Focal adhesion kinase (FAK) is a protein tyrosine kinase enriched in focal adhesions, which plays a critical role in integrin-dependent cell motility and survival. The crucial step in its activation is autophosphorylation on Tyr-397, which promotes the recruitment of several enzymes including Src family kinases and the activation of multiple signaling pathways. We found in a yeast two-hybrid screen that the N-terminal domain of FAK interacted with protein inhibitor of activated STAT1 (PIAS1). This interaction was confirmed and shown to be direct using in vitro assays. PIAS1 was co-immunoprecipitated with FAK from transfected cells and brain extracts. PIAS1 has recently been recognized as a small ubiquitin-like modifier (SUMO) ligase. In the presence of PIAS1 and SUMO-1, FAK was sumoylated in intact cells, whereas PYK2, a closely related enzyme, was not. Sumoylation occurred on Lys-152, a residue conserved in FAK during evolution. Sumoylated FAK, like PIAS1, was recovered predominantly from the nuclear fraction. Sumoylation did not require the catalytic activity or autophosphorylation of FAK. In contrast, sumoylation increased dramatically the ability of FAK to autophosphorylate in intact cells and in immune precipitate kinase assays. Endogenous FAK was sumoylated in the presence of PIAS1 and SUMO-1 independently of cell adhesion, and autophosphorylation of sumoylated FAK was persistently increased in suspended cells. These observations show that sumoylation controls the activity of a protein kinase and suggest that FAK may play a novel role in signaling between the plasma membrane and the nucleus. Focal adhesion kinase (FAK) 1The abbreviations used are: FAKfocal adhesion kinaseGSTglutathione S-transferaseHAhemagglutininSTATsignal transducer and activator of transcriptionPIAS1protein inhibitor of activated STAT1PYK2proline-rich tyrosine kinase 2SUMOsmall ubiquitin-like modifier proteinE3ubiquitin-protein ligaseP-Tyrphosphorylated form of tyrosine. is a non-receptor cytoplasmic tyrosine kinase of 125 kDa (1Schaller M.D. Borgman C.A. Cobb B.S. Vines R.R. Reynolds A.B. Parsons J.T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 5192-5196Crossref PubMed Scopus (1296) Google Scholar, 2Hanks S.K. Calalb M.B. Harper M.C. Patel S.K. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 8487-8491Crossref PubMed Scopus (735) Google Scholar) implicated in integrin-mediated signal transduction (reviewed in Refs. 3Hanks S.K. Polte T.R. Bioessays. 1997; 19: 137-145Crossref PubMed Scopus (442) Google Scholar, 4Parsons J.T. Martin K.H. Slack J.K. Taylor J.M. Weed S.A. Oncogene. 2000; 19: 5606-5613Crossref PubMed Scopus (571) Google Scholar, 5Schaller M.D. Biochim. Biophys. Acta. 2001; 1540: 1-21Crossref PubMed Scopus (507) Google Scholar). It is also activated by a variety of extracellular stimuli including G protein-coupled receptors and growth factor receptors (see Refs. 5Schaller M.D. Biochim. Biophys. Acta. 2001; 1540: 1-21Crossref PubMed Scopus (507) Google Scholar and 6Girault J.A. Costa A. Derkinderen P. Studler J.M. Toutant M. Trends Neurosci. 1999; 22: 257-263Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). In adherent mammalian cells in culture FAK is located in focal adhesions (1Schaller M.D. Borgman C.A. Cobb B.S. Vines R.R. Reynolds A.B. Parsons J.T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 5192-5196Crossref PubMed Scopus (1296) Google Scholar, 2Hanks S.K. Calalb M.B. Harper M.C. Patel S.K. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 8487-8491Crossref PubMed Scopus (735) Google Scholar) and appears important for the regulation of their turnover (7Ilic D. Furuta Y. Kanazawa S. Takeda N. Sobue K. Nakatsuji N. Nomura S. Fujimoto J. Okada M. Yamamoto T. Nature. 1995; 377: 539-544Crossref PubMed Scopus (1602) Google Scholar). FAK is critical for adhesion-dependent cell survival (8Frisch S.M. Vuori K. Ruoslahti E. Chan-Hui P.Y. J. Cell Biol. 1996; 134: 793-799Crossref PubMed Scopus (1008) Google Scholar) and integrin-mediated motility (9Sieg D.J. Hauck C.R. Schlaepfer D.D. J. Cell Sci. 1999; 112: 2677-2691Crossref PubMed Google Scholar). Its physiological importance is demonstrated by the embryonic mortality of FAK knockout mice (7Ilic D. Furuta Y. Kanazawa S. Takeda N. Sobue K. Nakatsuji N. Nomura S. Fujimoto J. Okada M. Yamamoto T. Nature. 1995; 377: 539-544Crossref PubMed Scopus (1602) Google Scholar), whereas recent work underlines its role in tumor invasiveness (10Hsia D.A. Mitra S.K. Hauck C.R. Streblow D.N. Nelson J.A. Ilic D. Huang S. Li E. Nemerow G.R. Leng J. Spencer K.S. Cheresh D.A. Schlaepfer D.D. J. Cell Biol. 2003; 160: 753-767Crossref PubMed Scopus (466) Google Scholar). Autophosphorylation at Tyr-397 is a crucial event for FAK biological function, because it creates a high affinity binding site for proteins harboring Src homology 2 (SH2) domains, such as Src and Fyn (11Cobb B.S. Schaller M.D. Leu T.H. Parsons J.T. Mol. Cell. Biol. 1994; 14: 147-155Crossref PubMed Scopus (496) Google Scholar), Grb7 (12Han D.C. Guan J.L. J. Biol. Chem. 1999; 274: 24425-24430Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar), and phosphatidylinositide 3′-OH-kinase, which activates the anti-apoptotic Akt pathway (13Chen H.C. Guan J.L. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10148-10152Crossref PubMed Scopus (486) Google Scholar, 14Akagi T. Murata K. Shishido T. Hanafusa H. Mol. Cell. Biol. 2002; 22: 7015-7023Crossref PubMed Scopus (61) Google Scholar). Following their binding to phospho-Tyr-397, Src or Fyn phosphorylate FAK at other tyrosine residues (15Calalb M.B. Polte T.R. Hanks S.K. Mol. Cell. Biol. 1995; 15: 954-963Crossref PubMed Google Scholar, 16Schlaepfer D.D. Jones K.C. Hunter T. Mol. Cell. Biol. 1998; 18: 2571-2585Crossref PubMed Scopus (359) Google Scholar) as well as associated proteins, thereby leading to the activation of several signaling pathways (see 5). focal adhesion kinase glutathione S-transferase hemagglutinin signal transducer and activator of transcription protein inhibitor of activated STAT1 proline-rich tyrosine kinase 2 small ubiquitin-like modifier protein ubiquitin-protein ligase phosphorylated form of tyrosine. In contrast to the recent progress in elucidating the signaling pathways downstream from FAK, relatively little is known about the molecular mechanisms regulating FAK activity. The tyrosine kinase domain of FAK occupies a central position in the molecule. The C-terminal region encompasses two prolinerich sequences, sites of multiple protein-protein interactions (see Ref. 5Schaller M.D. Biochim. Biophys. Acta. 2001; 1540: 1-21Crossref PubMed Scopus (507) Google Scholar) and the focal adhesion targeting domain (17Hildebrand J.D. Schaller M.D. Parsons J.T. J. Cell Biol. 1993; 123: 993-1005Crossref PubMed Scopus (363) Google Scholar). In contrast, the role of the N-terminal domain, which displays significant sequence similarity with the FERM (band 4.1, ezrin, radixin, and moesin) domain (18Girault J.A. Labesse G. Mornon J.P. Callebaut I. Trends Biochem. Sci. 1999; 24: 54-57Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar), is less well characterized. This domain has the capacity to interact with ezrin (19Poullet P. Gautreau A. Kadare G. Girault J.A. Louvard D. Arpin M. J. Biol. Chem. 2001; 276: 37686-37691Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar) and peptides mimicking intracellular regions of β-integrins (20Schaller M.D. Otey C.A. Hildebrand J.D. Parsons J.T. J. Cell Biol. 1995; 130: 1181-1187Crossref PubMed Scopus (557) Google Scholar). Deletion of this domain, or part of it, increases tyrosine phosphorylation and autophosphorylation of FAK, suggesting that it regulates FAK activity (21Eide B.L. Turck C.W. Escobedo J.A. Mol. Cell. Biol. 1995; 15: 2819-2827Crossref PubMed Scopus (164) Google Scholar, 22Chan P.Y. Kanner S.B. Whitney G. Aruffo A. J. Biol. Chem. 1994; 269: 20567-20574Abstract Full Text PDF PubMed Google Scholar, 23Toutant M. Costa A. Studler J.M. Kadare G. Carnaud M. Girault J.A. Mol. Cell. Biol. 2002; 22: 7731-7743Crossref PubMed Scopus (112) Google Scholar). To elucidate the role and partners of the N-terminal domain of FAK, we undertook a yeast two-hybrid screen and identified a novel interaction partner, PIAS1, a protein initially cloned as a specific inhibitor of activated STAT1 (24Liu B. Liao J. Rao X. Kushner S.A. Chung C.D. Chang D.D. Shuai K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 10626-10631Crossref PubMed Scopus (638) Google Scholar). PIAS family proteins have recently been shown to be ligases for small ubiquitin-like modifier proteins (SUMO) (25Schmidt D. Muller S. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 2872-2877Crossref PubMed Scopus (375) Google Scholar, 26Sapetschnig A. Rischitor G. Braun H. Doll A. Schergaut M. Melchior F. Suske G. EMBO J. 2002; 21: 5206-5215Crossref PubMed Scopus (230) Google Scholar). We report that PIAS1 induces the conjugation of SUMO-1 to FAK on Lys-152. SUMO-1 conjugation to FAK enhances the autophosphorylation capacity of the protein in vitro and in cells, independently of adhesion, suggesting a novel mode of regulation of this enzyme. Materials—Mouse monoclonal antibodies used were anti-FAK 4.47 (Upstate Biotechnology), anti-SUMO-1 (Zymed Laboratories Inc.), and anti-HA antibody (12CA5; Roche Molecular Biochemicals). Rabbit polyclonal antibodies directed against FAK were A-17 (1:500 for immunoblotting) and C-20 (1:500) (Santa Cruz Biotechnology) and anti-phos-pho-Tyr-397 (1:2000) (BIOSOURCE). Anti-PIAS1 serum was raised against a recombinant fusion protein, GST-ΔPIAS1, encompassing residues 402–651 of human PIAS1. Serum SL41 for specific immunoprecipitation of transfected FAK and serum against PYK2 were as described (27Derkinderen P. Toutant M. Burgaya F. Le Bert M. Siciliano J.C. de Franciscis V. Gelman M. Girault J.A. Science. 1996; 273: 1719-1722Crossref PubMed Scopus (158) Google Scholar, 28Siciliano J.C. Toutant M. Derkinderen P. Sasaki T. Girault J.A. J. Biol. Chem. 1996; 271: 28942-28946Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Anti-stathmin polyclonal antibody was a from A. N-terminal of FAK and PYK2 were cloned in and used as in yeast with a human brain were on and were and for growth in and for activity. for were used for of yeast including to the of the and and were by PIAS1 from from J. of and from and was by a FAK sequence from cell PIAS1 was by of PIAS1 from with and the of of FAK with was with Cell and and cells were and transfected with of culture as described M. Costa A. Studler J.M. Kadare G. Carnaud M. Girault J.A. Mol. Cell. Biol. 2002; 22: 7731-7743Crossref PubMed Scopus (112) Google Scholar). the of transfected 2 of M. Costa A. Studler J.M. Kadare G. Carnaud M. Girault J.A. Mol. Cell. Biol. 2002; 22: 7731-7743Crossref PubMed Scopus (112) Google Scholar) or 2 of from J. and the of was with were of and suspended cells M. Costa A. Studler J.M. Kadare G. Carnaud M. Girault J.A. Mol. Cell. Biol. 2002; 22: 7731-7743Crossref PubMed Scopus (112) Google Scholar) and cell D. 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J. 2000; PubMed Google Scholar). of a between PIAS1 and FAK N-terminal by and in yeast two-hybrid screen of a human brain using the N-terminal domain of FAK as a of 2 which 125 were for were for using domain of or with the N-terminal domain of PYK2 kinase closely related to or with as a for the with FAK N-terminal domain as of for the proteins and and we identified proteins as partners of FAK N-terminal were found to human PIAS1 C-terminal region to as PIAS1 is the of a small protein family with a central and a less conserved C-terminal region to K. Oncogene. 2000; 19: PubMed Scopus Google Scholar). PIAS1 regulates the activity of several transcription including STAT1 (24Liu B. Liao J. Rao X. Kushner S.A. Chung C.D. Chang D.D. Shuai K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 10626-10631Crossref PubMed Scopus (638) Google Scholar), (25Schmidt D. Muller S. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 2872-2877Crossref PubMed Scopus (375) Google Scholar), (25Schmidt D. Muller S. Proc. 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Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) the that the interaction was the of not be To that the interaction was we used as a to a of recombinant GST-ΔPIAS1, region of a protein to Ref. J.A. Labesse G. Mornon J.P. Callebaut I. Trends Biochem. Sci. 1999; 24: 54-57Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar), or and protein not the other proteins on the including the molecular (see This demonstrated that the interaction between FAK and PIAS1 did not require FAK and PIAS1 in and the between FAK and PIAS1 transfected in cells, using immunoprecipitation with serum by with anti-FAK monoclonal FAK was in the PIAS1 immune precipitate the two proteins were specific interaction between FAK and PIAS1 was also in to immunoprecipitation with serum by FAK These demonstrated that FAK and PIAS1 proteins interact in transfected cells and that the proteins also interact in In the of co-immunoprecipitated protein were suggesting that a of FAK is associated with PIAS1. FAK by SUMO-1 in the of PIAS1 has been shown to interact with SUMO-1 and its leading to the of several proteins including (25Schmidt D. Muller S. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 2872-2877Crossref PubMed Scopus (375) Google Scholar, T. T. H. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. X. M. D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is a small protein that be to the of a residue on a protein pathway that of sumoylation appears to play multiple that from of F. Cell Biol. 2000; PubMed Scopus Google Scholar). We the that PIAS1 as ligase FAK, using cells with FAK and of PIAS1. of SUMO-1 was in because cells small of SUMO-1 F. Cell Biol. 2000; PubMed Scopus Google Scholar). a that enzymes M. Nature. 1999; PubMed Scopus Google Scholar, T. S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), was to the to sumoylated Sumoylation of FAK, which as a was by the of with increased molecular to the at about kDa the of PIAS1 was increased in a The was also with monoclonal antibody that it to sumoylated FAK. To that the high molecular to sumoylated FAK, transfected cell were with anti-FAK serum and with anti-FAK and anti-SUMO-1 monoclonal antibodies The protein was as as FAK protein and by anti-FAK and anti-SUMO-1 antibodies that it to FAK. The of the FAK was with the of a SUMO-1 molecule. These that in transfected cells FAK is sumoylated in the presence of PIAS1, which as ligase. PIAS1 Sumoylation of FAK at of proteins at specific in in a M. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), in which is a residue and is In is by G. J. Cell Biol. 1999; PubMed Scopus Google Scholar, E. Y. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). We found in the FAK sequence a It is that this was not FAK proteins of in which the sequence is also in and in which is less in the To was the site for conjugation of we this residue to The FAK protein, FAK was not by SUMO-1 to of FAK, that was the sumoylation of the of SUMO-1 to FAK not its interaction with PIAS1, because FAK and FAK were to interact with 2 and PYK2, a tyrosine kinase closely related to FAK sequence which a to and did not interact with PIAS1 in yeast two (see was not sumoylated in cells not demonstrated that PIAS1 induces the sumoylation of FAK on Lys-152, a site conserved in FAK from Sumoylated FAK in the and Sumoylation of Its Autophosphorylation and in the F. Cell Biol. 2000; PubMed Scopus Google Scholar). In transfected cells, PIAS1, a predominantly nuclear protein N. U. Mol. Cell. Biol. 2002; 22: PubMed Scopus Google Scholar), was found in the nuclear 5). The of was also in this nuclear suggesting that sumoylation of FAK occurred in the as for sumoylated proteins F. Cell Biol. 2000; PubMed Scopus Google Scholar). FAK is a tyrosine kinase by we phosphorylation kinase activity were important for its autophosphorylation of FAK its kinase activity was for its as shown by the of FAK with or and In of FAK with increased capacity to autophosphorylation F. Toutant M. Studler J.M. Costa A. Le Bert M. Gelman M. Girault J.A. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) were sumoylated to the as the not show that conjugation of SUMO-1 to FAK is a of its autophosphorylation and catalytic activity. Sumoylation of FAK Its Sumoylation has been to on It protein-protein interactions J. G. J. Cell Biol. 1998; PubMed Scopus Google Scholar), on the residue J.M. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, T. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), A. H. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), or the biological activity of transcription such as or (25Schmidt D. Muller S. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 2872-2877Crossref PubMed Scopus (375) Google Scholar, 26Sapetschnig A. Rischitor G. Braun H. Doll A. Schergaut M. Melchior F. Suske G. EMBO J. 2002; 21: 5206-5215Crossref PubMed Scopus (230) Google Scholar, S. M. F. Y. A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. S. C.A. EMBO J. 1999; 18: PubMed Scopus Google Scholar, M. A. V. P. M. G. EMBO J. 1999; 18: PubMed Scopus Google Scholar) or of enzymes including G. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). the autophosphorylation of FAK is step in its activation and function, we it was by SUMO-1 We the of phosphorylation of sumoylated and FAK in cells with FAK, SUMO-1, and of PIAS1 using antibody that the phosphorylated form of Tyr-397 M. Costa A. Studler J.M. Kadare G. Carnaud M. Girault J.A. Mol. Cell. Biol. 2002; 22: 7731-7743Crossref PubMed Scopus (112) Google Scholar) of sumoylated FAK a Tyr-397 phosphorylation signal was in as with FAK of PIAS1 by did not because FAK which PIAS1 is not sumoylated (see a of autophosphorylation as FAK sumoylation did not on phosphorylation (see show that sumoylation of FAK increased the phosphorylation of Tyr-397 in intact cells. FAK autophosphorylation on Tyr-397 is known to a high affinity binding site for the Src homology 2 domain of Src and Fyn (11Cobb B.S. Schaller M.D. Leu T.H. Parsons J.T. Mol. Cell. Biol. 1994; 14: 147-155Crossref PubMed Scopus (496) Google Scholar). These kinases phosphorylate other tyrosine residues in FAK, including and in the activation of the kinase domain, thereby phosphorylation of Tyr-397 E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). the of FAK sumoylation did not to Src family because were in the presence of inhibitor of and phosphorylation of in sumoylated FAK was not phosphorylation of Tyr-397 in cells from of its phosphorylation or of its To the of the phosphorylation of we in vitro kinase and FAK were and the immune were by the of tyrosine and in the presence of M. Studler J.M. Burgaya F. Costa A. P. Gelman M. Girault J.A. Biochem. J. 2000; PubMed Google Scholar). proteins were and by for FAK and by and The of in was in FAK for the of the of the membrane with antibody confirmed that the increased of in sumoylated FAK with high of for the increased of phosphorylation of on Tyr-397 with FAK be for by in its ability to In contrast, sumoylation increased the activity of FAK in vitro sumoylated FAK the mechanisms of activation of FAK autophosphorylation by the conjugation of not may a of the role of the N-terminal FERM domain a of the interactions P.Y. Kanner S.B. Whitney G. Aruffo A. J. Biol. Chem. 1994; 269: 20567-20574Abstract Full Text PDF PubMed Google Scholar, 23Toutant M. Costa A. Studler J.M. Kadare G. Carnaud M. Girault J.A. Mol. Cell. Biol. 2002; 22: 7731-7743Crossref PubMed Scopus (112) Google Scholar). Sumoylation Autophosphorylation of Endogenous FAK of Cell we cells PIAS1 and SUMO-1, we found that a significant of FAK was sumoylated in the of transfected FAK, sumoylated FAK was enriched in the nuclear not FAK activation is by and is cell adhesion-dependent M.D. Biochim. Biophys. Acta. 2001; 1540: 1-21Crossref PubMed Scopus (507) Google Scholar), we the of adhesion on The of FAK in the sumoylated form was in or suspended cells in the presence of PIAS1 and SUMO-1 whereas Tyr-397 of FAK was cell autophosphorylation of was These that sumoylation of FAK and the increased autophosphorylation independently of cell of FAK with PIAS1 and that PIAS1 with FAK and its in the FAK is a cytoplasmic protein that has a well at the plasma the presence of of FAK and of the protein in the has been suggesting that FAK may have a role in the A. I. Biochem. Biophys. 2002; PubMed Scopus Google Scholar, X. Li F. 2003; PubMed Scopus Google Scholar). be that FAK a that its nuclear sumoylation in the presence of PIAS1. the related protein PYK2 has recently been shown to a in the A. J. Biochem. Mol. Biol. 2003; PubMed Scopus Google Scholar, H. Sasaki H. M. Sasaki T. Cell 2002; PubMed Scopus Google Scholar), its mechanisms to be it be important to the of FAK in the be by interaction with other proteins, including PIAS1. little is known about the regulation of PIAS1 or activity. of proteins associated with plasma membrane adhesion receptors known to a to the and to nuclear J. Cell Biol. 2001; PubMed Scopus Google Scholar, 2003; PubMed Scopus Google Scholar). It is to that FAK may have a and the of a tyrosine kinase to signal at focal adhesions as well as in the nucleus. autophosphorylation is the critical step in FAK activation and because sumoylation dramatically FAK sumoylation of FAK step the of FAK in the nucleus. To this it be critical to of FAK in the or in its K. H. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In show that FAK be sumoylated in the presence of PIAS1, nuclear suggesting that FAK may play a novel role in signaling between the plasma membrane and the nucleus. We for the of yeast two-hybrid and for the for and for and for in
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