PTP1B Regulates Cortactin Tyrosine Phosphorylation by Targeting Tyr446

The emergence of protein-tyrosine phosphatase 1B (PTP1B) as a potential drug target for treatment of diabetes, obesity, and cancer underlies the importance of understanding its full range of cellular functions. Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr446, the regulation and function of which have not previously been characterized. We show that phosphorylation of cortactin Tyr446 is induced by hyperosmolarity and potentiates apoptotic signaling during prolonged hyperosmotic stress. This study advances the importance of Tyr446 in the regulation of cortactin and provides a potential mechanism to explain the effects of PTP1B on processes including cell adhesion, migration, and tumorigenesis. The emergence of protein-tyrosine phosphatase 1B (PTP1B) as a potential drug target for treatment of diabetes, obesity, and cancer underlies the importance of understanding its full range of cellular functions. Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr446, the regulation and function of which have not previously been characterized. We show that phosphorylation of cortactin Tyr446 is induced by hyperosmolarity and potentiates apoptotic signaling during prolonged hyperosmotic stress. This study advances the importance of Tyr446 in the regulation of cortactin and provides a potential mechanism to explain the effects of PTP1B on processes including cell adhesion, migration, and tumorigenesis. Protein-tyrosine phosphatase (PTP) 4The abbreviations used are: PTP, protein-tyrosine phosphatase; SH3, Src homology 3; GST, glutathione S-transferase; WT, wild-type; DMEM, Dulbecco's modified Eagle's medium; EGF, epidermal growth factor. 4The abbreviations used are: PTP, protein-tyrosine phosphatase; SH3, Src homology 3; GST, glutathione S-transferase; WT, wild-type; DMEM, Dulbecco's modified Eagle's medium; EGF, epidermal growth factor. 1B is recognized as an important regulator of metabolic signaling in mice. Ablation of the gene encoding PTP1B, Ptpn1, causes tissue-specific hypersensitivity to insulin and leptin, resulting in resistance to diabetes and obesity (1Elchebly M. Payette P. Michaliszyn E. Cromlish W. Collins S. Loy A.L. Normandin D. Cheng A. Himms-Hagen J. Chan C.C. Ramachandran C. Gresser M.J. Tremblay M.L. Kennedy B.P. Science. 1999; 283: 1544-1548Crossref PubMed Scopus (1882) Google Scholar, 2Bence K.K. Delibegovic M. Xue B. Gorgun C.Z. Hotamisligil G.S. Neel B.G. Kahn B.B. Nat. Med. 2006; 12: 917-924Crossref PubMed Scopus (484) Google Scholar). PTP1B is a ubiquitously expressed enzyme that is localized to the cytoplasmic face of the endoplasmic reticulum (3Frangioni J.V. Heahm P.H. Shifrin V. Jost C.A. Neel B.G. Cell. 1992; 68: 545-560Abstract Full Text PDF PubMed Scopus (500) Google Scholar). Its catalytic domain can directly dephosphorylate and inactivate the insulin receptor and other receptor and non-receptor protein-tyrosine kinases (4Blanchetot C. Chagnon M. Dubé N. Hallé M. Tremblay M.L. Methods (San Diego). 2005; 35: 44-53Crossref PubMed Scopus (134) Google Scholar). Despite the proto-oncogenic functions of many of these protein-tyrosine kinases, Ptpn1-null mice are not prone to tumorigenesis. On the contrary, two recent studies found that mice lacking PTP1B are markedly resistant to mammary tumorigenesis induced by active mutants of the receptor tyrosine kinase ErbB2 (5Julien S.G. Dubé N. Read M. Penney J. Paquet M. Han Y. Kennedy B.P. Muller W.J. Tremblay M.L. Nat. Genet. 2007; 39: 338-346Crossref PubMed Scopus (266) Google Scholar, 6Bentires-Alj M. Neel B.G. Cancer Res. 2007; 67: 2420-2424Crossref PubMed Scopus (183) Google Scholar). The effect of PTP1B deficiency in these cancer models has highlighted its diverse cellular functions. One emerging role of PTP1B is in the regulation of the actin cytoskeleton. Early studies in fibroblasts showed that PTP1B is required for proper cell adhesion and spreading on extracellular matrix proteins (7Cheng A. Bal G.S. Kennedy B.P. Tremblay M.L. J. Biol. Chem. 2001; 276: 25848-25855Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Cell adhesion to the extracellular matrix is mediated largely by cell-surface integrins, which initiate signaling cascades and orchestrate changes in the actin cytoskeleton at adhesive contacts. Protein-tyrosine kinases involved in transmission of integrin signals, including c-Src (8Bjorge J.D. Pang A. Fujita D.J. J. Biol. Chem. 2000; 275: 41439-41446Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar), focal adhesion kinase (9Zhang Z. Lin S.Y. Neel B.G. Haimovich B. J. Biol. Chem. 2006; 281: 1746-1754Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar), and Csk (10Arias-Salgado E.G. Haj F. Dubois C. Moran B. Kasirer-Friede A. Furie B.C. Furie B. Neel B.G. Shattil S.J. J. Cell Biol. 2005; 170: 837-845Crossref PubMed Scopus (99) Google Scholar), have been proposed as PTP1B substrates; however, none has consistently been shown to be hyperphosphorylated in the absence of PTP1B. It is tempting to speculate that, rather than regulating upstream signaling, PTP1B may directly target one or more non-protein-tyrosine kinase actin regulatory proteins. Cortactin was identified as a prominent tyrosine phosphoprotein in cells expressing the active protein-tyrosine kinase v-Src (11Wu H. Reynolds A.B. Kanner S.B. Vines R.R. Parsons J.T. Mol. Cell. Biol. 1991; 11: 5113-5124Crossref PubMed Scopus (371) Google Scholar). It has subsequently been implicated in various processes requiring dynamic actin assembly, including cell adhesion and migration, vesicular transport, and microbial infection (12Buday L. Downward J. Biochim. Biophys. Acta. 2007; 1775: 263-273PubMed Google Scholar, 13Selbach M. Backert S. Trends Microbiol. 2005; 13: 181-189Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Cortactin exerts its effects on the actin cytoskeleton by interacting directly with the Arp2/3 complex (via its N-terminal acidic domain) (see Fig. 3), F-actin (via a central repeat region), and other actin regulatory proteins such as N-WASP and MIM (via its C-terminal SH3 domain) (12Buday L. Downward J. Biochim. Biophys. Acta. 2007; 1775: 263-273PubMed Google Scholar). A variety of additional binding partners mediate the effects of cortactin in specific contexts, including receptor tyrosine kinase down-regulation and cell-cell adhesion. Cortactin is tyrosine-phosphorylated in response to a wide range of stimuli that induce cytoskeletal rearrangement, including growth factor stimulation, cell adhesion, and hyperosmotic stress (14Lua B.L. Low B.C. FEBS Lett. 2005; 579: 577-585Crossref PubMed Scopus (111) Google Scholar). Src phosphorylates murine cortactin predominantly at three key sites in vitro, Tyr421, Tyr466, and Tyr482 (corresponding to Tyr421, Tyr470, and Try486 in human cortactin), resulting in decreased actin cross-linking activity (15Huang C. Liu J. Haudenschild C.C. Zhan X. J. Biol. Chem. 1998; 273: 25770-25776Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar). The combined mutation of these three residues abolishes tyrosine phosphorylation of cortactin in cells under various conditions (15Huang C. Liu J. Haudenschild C.C. Zhan X. J. Biol. Chem. 1998; 273: 25770-25776Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 16Kapus A. Di Ciano C. Sun J. Zhan X. Kim L. Wong T.W. Rotstein O.D. J. Biol. Chem. 2000; 275: 32289-32298Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 17Fan L. Di Ciano-Oliveira C. Weed S.A. Craig A.W. Greer P.A. Rotstein O.D. Kapus A. Biochem. J. 2004; 380: 581-591Crossref PubMed Scopus (63) Google Scholar). Thus, these Src sites have been the focus for functional characterization of cortactin tyrosine phosphorylation. Nonetheless, several mass spectrometry-phosphoproteomic studies have identified additional phosphorylated tyrosine residues (18Wolf-Yadlin A. Hautaniemi S. Lauffenburger D.A. White F.M. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5860-5865Crossref PubMed Scopus (430) Google Scholar, 19Rush J. Moritz A. Lee K.A. Guo A. Goss V.L. Spek E.J. Zhang H. Zha X.M. Polakiewicz R.D. Comb M.J. Nat. Biotechnol. 2005; 23: 94-101Crossref PubMed Scopus (942) Google Scholar, 20Hinsby A.M. Olsen J.V. Bennett K.L. Mann M. Mol. Cell. Proteomics. 2003; 2: 29-36Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 21Zhang Y. Wolf-Yadlin A. Ross P.L. Pappin D.J. Rush J. Lauffenburger D.A. White F.M. Mol. Cell. Proteomics. 2005; 4: 1240-1250Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar, 22Amanchy R. Kalume D.E. Iwahori A. Zhong J. Pandey A. J. Proteome Res. 2005; 4: 1661-1671Crossref PubMed Scopus (99) Google Scholar, 23Wolf-Yadlin A. Kumar N. Zhang Y. Hautaniemi S. Zaman M. Kim H.D. Grantcharova V. Lauffenburger D.A. White F.M. Mol. Syst. Biol. 2006; 2: 54Crossref PubMed Scopus (198) Google Scholar, 24Wang Y. Du D. Fang L. Yang G. Zhang C. Zeng R. Ullrich A. Lottspeich F. Chen Z. EMBO J. 2006; 25: 5058-5070Crossref PubMed Scopus (60) Google Scholar). A number of individual phosphotyrosine sites have been reported independently in different cell types and in response to diverse stimuli, but their regulation and function remain to be investigated. In this study, we have identified cortactin as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at a previously uncharacterized tyrosine residue, Tyr446. We show that PTP1B regulates cortactin phosphorylation induced by hyperosmolarity and that Tyr446 is required for protection from apoptosis induced by hyperosmotic stress. Our results are the first to implicate a specific PTP in the regulation of cortactin, and they reveal a novel mechanism by which PTP1B may influence the cytoskeleton. Antibodies—The following antibodies were used: anti-cortactin clone 4F11 and anti-phosphotyrosine clone 4G10 (Millipore), anti-cortactin phospho-Tyr421 (Invitrogen), anti-PTP1B clone 15 (BD Transduction Laboratories), and anti-GST (Z-5, Santa Cruz Biotechnology, Inc.). An anti-cortactin polyclonal antibody (used exclusively for supplemental Fig. 1) was purchased from Cell Signaling Technology. The polyclonal antibody specific for human cortactin phospho-Tyr446 was prepared by Quality Controlled Biochemicals (Hopkinton, MA). Plasmids—Expression plasmids (pEBG) encoding GST-tagged human PTP1B (WT and D181A) were described previously (25Simoncic P.D. Lee-Loy A. Barber D.L. Tremblay M.L. McGlade C.J. Curr. Biol. 2002; 12: 446-453Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar). To prepare additional GST-tagged PTP constructs, cDNAs from pEF-BOS-TCPTP (WT and D182A) and pcDNA4-PTP-PEST (WT and D199A) were amplified by PCR, introducing BamHI (5′) and NotI (3′) sites, and subsequently subcloned into the pEBG vector. Untagged expression constructs (pcDNA3) encoding human WT cortactin and mutants Y421F, Y470F, and Y486F were a kind gift of Dr. Scott Weed (West Virginia University). Additional cortactin mutants were prepared by site-directed mutagenesis (QuikChange kit, Stratagene). Plasmids used for expression of untagged human PTP1B (WT or C215S, pcDNA3.1) were described previously (26Stuible M. Zhao L. Aubry I. Schmidt-Arras D. Bohmer F.D. Li C.J. Tremblay M.L. ChemBioChem. 2007; 8: 179-186Crossref PubMed Scopus (32) Google Scholar). Insert sequences of all constructs were confirmed by DNA sequencing. 5The sequences of primers used for cloning and mutagenesis are available on request. Substrate Trapping—Cell lines were routinely maintained in DMEM containing 10% fetal bovine serum and 50 μg/ml gentamicin (all from Invitrogen). For trapping of endogenous cortactin, HeLa or COS-7 cells (plated at 5 × 105 cells/6-cm dish) were transfected with 4.8 μg of DNA (4 μg of pEBG-PTP1B and 0.8 μg of v-Src or a control empty vector) using Lipofectamine 2000 (Invitrogen) following the manufacturer's protocol. For GST-PTP/cortactin coexpression COS-7 cells × in were transfected with μg of and μg of were as described A. N. P.D. Lee-Loy A. McGlade C.J. Kennedy B.P. Tremblay M.L. Cell. 2002; 2: Full Text Full Text PDF PubMed Scopus Google Scholar). and HeLa cells of were transfected with μg of (WT or (WT or or a control empty and for in growth were in DMEM for to treatment with hyperosmotic in or human For HeLa cells were for in DMEM by in DMEM containing a PTP1B as described previously J. D. G. E. Kennedy B.P. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar). The hyperosmotic used for cell the of For all cells were and were by as described previously (26Stuible M. Zhao L. Aubry I. Schmidt-Arras D. Bohmer F.D. Li C.J. Tremblay M.L. ChemBioChem. 2007; 8: 179-186Crossref PubMed Scopus (32) Google Scholar). cells in were transfected with (WT or cells were and at in a were to for and subsequently in fetal bovine DMEM for to treatment with hyperosmotic in the activity was using the following the manufacturer's protocol. of Cortactin as a PTP1B novel PTP1B a was in which GST-tagged WT PTP1B or mutant was in COS-7 cells with The of WT PTP1B with its is is a catalytic residue, and the trapping mutant is to a complex with phosphorylated target proteins. The proteins to these two of PTP1B were using glutathione the cell of COS-7 cells expressing v-Src tyrosine as by with an anti-phosphotyrosine antibody WT PTP1B not with of these proteins the mutant to two of and for we found that cortactin PTP1B and that its mass the we by anti-phosphotyrosine The trapping mutant of PTP1B was to endogenous cortactin in HeLa and COS-7 cells The of cortactin expressed in COS-7 cells than that in HeLa An antibody that human cortactin was used to binding of PTP1B to cortactin in HeLa cells Fig. In cell expression of v-Src but was not for the that the phosphorylation of cortactin is for An of WT PTP1B with cortactin was that many of its cortactin and WT PTP1B not a PTP1B to the of A. J. N. I. A. A. J. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). We the of the by the binding of cortactin to two other and is the enzyme to PTP1B, and is predominantly many of its including receptor tyrosine kinases and and of with PTP1B (4Blanchetot C. Chagnon M. Dubé N. Hallé M. Tremblay M.L. Methods (San Diego). 2005; 35: 44-53Crossref PubMed Scopus (134) Google Scholar). is a cytoplasmic PTP that is a regulator of the actin cytoskeleton. The WT and trapping mutant of PTP1B, and were as proteins in COS-7 cells with WT cortactin using glutathione cortactin was in cells expressing PTP1B Thus, the the to with cortactin is specific to PTP1B. of the the site on cortactin, we cortactin mutants lacking the SH3 domain or the be by PTP1B Despite potential the cortactin SH3 domain and the PTP1B the mutant binding to PTP1B of of PTP1B not its to cortactin not In of the cortactin including the SH3 and the binding of PTP1B The a of tyrosine residues including the Src sites mutants were for of these and binding to PTP1B was mutation of a tyrosine residue, Tyr446, the The results of binding were by mutants at two of the Src sites, and binding to PTP1B Src site Y470F, as as and effects on the that Tyr446 is the binding additional residues may by the phosphorylation of Tyr446. of a for Cortactin studies have identified cortactin phosphorylated at Tyr446 (18Wolf-Yadlin A. Hautaniemi S. Lauffenburger D.A. White F.M. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5860-5865Crossref PubMed Scopus (430) Google Scholar, 19Rush J. Moritz A. Lee K.A. Guo A. Goss V.L. Spek E.J. Zhang H. Zha X.M. Polakiewicz R.D. Comb M.J. Nat. Biotechnol. 2005; 23: 94-101Crossref PubMed Scopus (942) Google Scholar, 20Hinsby A.M. Olsen J.V. Bennett K.L. Mann M. Mol. Cell. Proteomics. 2003; 2: 29-36Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 21Zhang Y. Wolf-Yadlin A. Ross P.L. Pappin D.J. Rush J. Lauffenburger D.A. White F.M. Mol. Cell. Proteomics. 2005; 4: 1240-1250Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar, 22Amanchy R. Kalume D.E. Iwahori A. Zhong J. Pandey A. J. Proteome Res. 2005; 4: 1661-1671Crossref PubMed Scopus (99) Google Scholar, 24Wang Y. Du D. Fang L. Yang G. Zhang C. Zeng R. Ullrich A. Lottspeich F. Chen Z. EMBO J. 2006; 25: 5058-5070Crossref PubMed Scopus (60) Google Scholar), and of cortactin sequences that Tyr446 has been results that Tyr446 is a important site for the regulation of To the role of PTP1B in cortactin a polyclonal antibody for human cortactin phospho-Tyr446 was prepared by of with a The of the antibody was using from transfected HeLa cells with The cortactin, which to the of the human E. Zhan X. E. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), on than the endogenous expressed in these showed that the antibody endogenous and WT cortactin, but not the mutant The of the antibody with cortactin was with a at a of 15 results that Tyr446 is a target of signaling and that this novel antibody is specific for this PTP1B Cortactin we found that PTP1B decreased cortactin phosphorylation in response to not the receptor and other receptor tyrosine kinases that cortactin phosphorylation are of PTP1B. Thus, the effect of PTP1B in this is to its activity on upstream receptor tyrosine kinases as as on cortactin can induce tyrosine phosphorylation of cortactin independently of receptor tyrosine Cell by hyperosmolarity to of the and cytoplasmic protein-tyrosine kinases A. Di Ciano C. Sun J. Zhan X. Kim L. Wong T.W. Rotstein O.D. J. Biol. Chem. 2000; 275: 32289-32298Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). was to cortactin at the previously identified Src sites, Tyr421, Tyr470, and mutation of these residues cortactin tyrosine phosphorylation A. Di Ciano C. Sun J. Zhan X. Kim L. Wong T.W. Rotstein O.D. J. Biol. Chem. 2000; 275: 32289-32298Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). results show that Tyr446 is under these treatment with hyperosmotic induced Tyr446 phosphorylation in HeLa cells expressing WT cortactin or with an antibody specific for showed that, as this site was phosphorylated in response to we found that the mutation in decreased phosphorylation that the phosphorylation of these residues is To the role of PTP1B in this we its expression or activity cortactin phosphorylation. of WT PTP1B phosphorylation at Tyr446 and an mutant of PTP1B of cells with a PTP1B phosphorylation of these sites of from showed that treatment in an in Tyr446 phosphorylation at the and with hyperosmotic Thus, the cellular effects of PTP1B and are with its characterization as a cortactin of Cortactin Tyr446 of the actin cytoskeleton is a mechanism in cells to a hyperosmotic Nonetheless, prolonged to apoptotic cell in a variety of cell types J.D. 2007; PubMed Scopus Google Scholar). A recent study showed that a tyrosine on the protein-tyrosine kinase focal adhesion phosphorylated during hyperosmotic is important for protection from apoptosis R. E. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). cortactin is tyrosine-phosphorylated in response to hyperosmolarity Ciano C. Z. A. Zhan X. Rotstein O.D. A. Kapus A. J. 2002; 283: PubMed Scopus Google Scholar), we cortactin Tyr446 a induced apoptosis in HeLa cells as by a of cortactin in a in with cells the WT This that mutation of Tyr446 potentiates apoptotic signaling in HeLa cells under hyperosmotic stress. The effect of PTP1B on the of diabetes, obesity, and tumorigenesis in mice has on its potential as a the by which of its cellular including the of matrix adhesion, remain Here, we have shown that the actin regulatory cortactin is a target of PTP1B. In COS-7 cells expressing the trapping mutant of PTP1B binds to cortactin, at and a of This of is the of tyrosine in these cells and the of PTP1B. identified as a PTP1B substrate in fibroblasts using a N. Cheng A. Tremblay M.L. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). on the of we that the is not and we are its The of PTP1B to cortactin is not by the and The of the is by the that their binding largely on a tyrosine residue, Tyr446. that cortactin Tyr446 is a phosphorylation phospho-Tyr446 have been following or of receptor tyrosine kinases (18Wolf-Yadlin A. Hautaniemi S. Lauffenburger D.A. White F.M. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5860-5865Crossref PubMed Scopus (430) Google Scholar, 20Hinsby A.M. Olsen J.V. Bennett K.L. Mann M. Mol. Cell. Proteomics. 2003; 2: 29-36Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 21Zhang Y. Wolf-Yadlin A. Ross P.L. Pappin D.J. Rush J. Lauffenburger D.A. White F.M. Mol. Cell. Proteomics. 2005; 4: 1240-1250Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar, 23Wolf-Yadlin A. Kumar N. Zhang Y. Hautaniemi S. Zaman M. Kim H.D. Grantcharova V. Lauffenburger D.A. White F.M. Mol. Syst. Biol. 2006; 2: 54Crossref PubMed Scopus (198) Google as as in cells with a PTP J. Moritz A. Lee K.A. Guo A. Goss V.L. Spek E.J. Zhang H. Zha X.M. Polakiewicz R.D. Comb M.J. Nat. Biotechnol. 2005; 23: 94-101Crossref PubMed Scopus (942) Google Scholar, 22Amanchy R. Kalume D.E. Iwahori A. Zhong J. Pandey A. J. Proteome Res. 2005; 4: 1661-1671Crossref PubMed Scopus (99) Google Scholar, 24Wang Y. Du D. Fang L. Yang G. Zhang C. Zeng R. Ullrich A. Lottspeich F. Chen Z. EMBO J. 2006; 25: 5058-5070Crossref PubMed Scopus (60) Google Scholar). Here, using we have confirmed that Tyr446 is a target of receptor signaling and shown that is phosphorylated in response to hyperosmotic stress. is that cortactin is phosphorylated in a with phospho-Tyr421 as a site for to D. Li M. Parsons J.T. Weed S.A. Mol. Biol. Cell. 2003; PubMed Scopus Google Scholar). that Tyr446 an additional mass studies have in several Tyr446 as the tyrosine-phosphorylated cortactin A.M. Olsen J.V. Bennett K.L. Mann M. Mol. Cell. Proteomics. 2003; 2: 29-36Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 21Zhang Y. Wolf-Yadlin A. Ross P.L. Pappin D.J. Rush J. Lauffenburger D.A. White F.M. Mol. Cell. Proteomics. 2005; 4: 1240-1250Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar, 24Wang Y. Du D. Fang L. Yang G. Zhang C. Zeng R. Ullrich A. Lottspeich F. Chen Z. EMBO J. 2006; 25: 5058-5070Crossref PubMed Scopus (60) Google Scholar). results show that in response to the phosphorylation of is on the of Tyr446. the trapping mutant of PTP1B binds to Tyr446 and not Tyr421, of PTP1B or of the WT enzyme we have shown that Tyr446 is required for protection of cells from to the potential importance of this in the regulation of actin In we to the Tyr446 and the Src sites as as of cortactin function on Tyr446 phosphorylation. An is that the regulation of cortactin to the effect of PTP1B on tumorigenesis in mice (5Julien S.G. Dubé N. Read M. Penney J. Paquet M. Han Y. Kennedy B.P. Muller W.J. Tremblay M.L. Nat. Genet. 2007; 39: 338-346Crossref PubMed Scopus (266) Google Scholar, 6Bentires-Alj M. Neel B.G. Cancer Res. 2007; 67: 2420-2424Crossref PubMed Scopus (183) Google Scholar). of a containing encoding human cortactin, is with human and cortactin has been implicated in the of cell and (12Buday L. Downward J. Biochim. Biophys. Acta. 2007; 1775: 263-273PubMed Google Scholar). It be to expression of cortactin the of cancer Nonetheless, the specific importance of cortactin regulation in this be a the effects of this enzyme on cancer cell the phosphorylation of Tyr446 be used as an in to the of In we have shown that PTP1B regulates cortactin tyrosine by directly Tyr446. This is the first a specific enzyme in the of this and its functional in the protection of cells during hyperosmotic stress. On the of these results and we that the of cortactin regulation by tyrosine which that Tyr421, Tyr470, and are of be to Tyr446. this study a novel mechanism by which PTP1B may a variety of cellular including regulation of the actin cytoskeleton. We Hallé for and for and for of the and Dr. Scott Weed for the human cortactin expression We are to for the PTP1B with

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