Consequences of Direct Versus Indirect Activation of Epidermal Growth Factor Receptor in Intestinal Epithelial Cells Are Dictated by Protein-tyrosine Phosphatase 1B

Abstract

The epidermal growth factor receptor (EGFR) is an integral regulator of many cellular functions. EGFR also acts as a central conduit for extracellular signals involving direct activation of the receptor by EGFR ligands or indirect activation by G protein-coupled receptor (GPCR)-stimulated transactivation of the EGFR. We have previously shown that EGFR negatively regulates epithelial chloride secretion as a result of transforming growth factor-α-mediated EGFR transactivation in response to muscarinic GPCR activation. Here we show that direct activation of the EGFR by EGFR ligands produces a different pattern of EGFR tyrosine phosphorylation and downstream phosphatidylinositol 3-kinase recruitment than GPCR-stimulated transactivation of the EGFR occurring via paracrine EGFR ligand release. Moreover, we demonstrate that this differential signaling and its consequences depend on protein-tyrosine phosphatase 1B activity. Thus protein-tyrosine phosphatase 1B governs differential recruitment of signaling pathways involved in EGFR regulation of epithelial ion transport. Our findings furthermore establish how divergent signaling outcomes can arise from the activation of a single receptor. The epidermal growth factor receptor (EGFR) is an integral regulator of many cellular functions. EGFR also acts as a central conduit for extracellular signals involving direct activation of the receptor by EGFR ligands or indirect activation by G protein-coupled receptor (GPCR)-stimulated transactivation of the EGFR. We have previously shown that EGFR negatively regulates epithelial chloride secretion as a result of transforming growth factor-α-mediated EGFR transactivation in response to muscarinic GPCR activation. Here we show that direct activation of the EGFR by EGFR ligands produces a different pattern of EGFR tyrosine phosphorylation and downstream phosphatidylinositol 3-kinase recruitment than GPCR-stimulated transactivation of the EGFR occurring via paracrine EGFR ligand release. Moreover, we demonstrate that this differential signaling and its consequences depend on protein-tyrosine phosphatase 1B activity. Thus protein-tyrosine phosphatase 1B governs differential recruitment of signaling pathways involved in EGFR regulation of epithelial ion transport. Our findings furthermore establish how divergent signaling outcomes can arise from the activation of a single receptor. All cell types rely on a limited set of receptors and signaling intermediates to translate extracellular information into appropriate acute and chronic changes in cellular behavior. Furthermore, many receptors mediate their effects via the secondary recruitment of other receptor types, including by stimulating the release of ligands for the downstream receptor (1Daub H. Weiss F.U. Wallasch C. Ullrich A. Nature. 1996; 379: 557-560Crossref PubMed Scopus (1329) Google Scholar, 2Prenzel N. Zwick E. Daub H. Leserer M. Abraham R. Wallasch C. Ullrich A. Nature. 1999; 402: 884-888Crossref PubMed Scopus (1501) Google Scholar). A well studied example of this paradigm relates to cross-talk between G-protein-coupled receptors and a variety of receptor tyrosine kinases. In some cases this receptor-tyrosine kinase “transactivation” results in different downstream consequences than does direct activation of the receptor with its endogenous ligand (3Barrett K.E. Smitham J. Traynor-Kaplan A. Uribe J.M. Am. J. Physiol. 1998; 274: C958-CC965Crossref PubMed Google Scholar, 4Keely S.J. Barrett K.E. J. Biol. Chem. 1999; 274: 33449-33454Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). However, a fundamental question remains as to how a single receptor, after activation by binding of either exogenous or endogenous ligand, can recruit distinct sets of downstream effectors and associated physiological outcomes. Epidermal growth factor receptor (EGFR) 2The abbreviations used are: EGFR, epidermal growth factor (EGF) receptor; CCh, carbachol; GPCR, G protein-coupled receptor; PAO, phenylarsine oxide; PTP1B, protein-tyrosine phosphatase 1B; siRNA, small interfering RNA; TGF-α, transforming growth factor α; PI3K, phosphatidylinositol 3-kinase. is one of four members of the ErbB receptor family, the other members being ErbB2, ErbB3, and ErbB4. Although ErbB2 has no known ligand of its own, it possesses the greatest enzymatic activity of the four isoforms and is the preferred dimerization partner for the other three receptors (5Graus-Porta D. Beerli R.R. Daly J.M. Hynes N.E. EMBO J. 1997; 16: 1647-1655Crossref PubMed Scopus (1309) Google Scholar). The complexity of ErbB receptor activity is amplified by the large number of peptide ligands described for these receptors. All of these peptides originate as transmembrane precursors that are then enzymatically cleaved, thus releasing mature soluble ligands, including the EGFR ligands, EGF, and transforming growth factor α (TGF-α). The latter is the most abundant EGFR ligand found in the gastrointestinal tract (6Beerli R.R. Hynes N.E. J. Biol. Chem. 1996; 271: 6071-6076Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 7Cartlidge S.A. Elder J.B. Br. J. Cancer. 1989; 60: 657-660Crossref PubMed Scopus (113) Google Scholar). After ligand binding, ErbB receptors undergo autophosphorylation and dimerization to form catalytically active homo- or heterodimers (8Zhang X. Gureasko J. Shen K. Cole P.A. Kuriyan J. Cell. 2006; 125: 1137-1149Abstract Full Text Full Text PDF PubMed Scopus (1191) Google Scholar). The composition of these receptor dimers dictates the recruitment of signaling pathways, adding another level of complexity to transduction of extracellular signals by this receptor family (5Graus-Porta D. Beerli R.R. Daly J.M. Hynes N.E. EMBO J. 1997; 16: 1647-1655Crossref PubMed Scopus (1309) Google Scholar, 9Lenferink A.E. Pinkas-Kramarski R. van De Poll M.L. van Vugt M.J. Klapper L.N. Tzahar E. Waterman H. Sela M. van Zoelen E.J. Yarden Y. EMBO J. 1998; 17: 3385-3397Crossref PubMed Scopus (343) Google Scholar). Downstream interaction with SH2 domain-containing molecules depends on the type of dimer formed, reflected in the ultimate recruitment of different signaling effectors such as mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI3K). In addition, after binding to the EGFR, different EGFR ligands have variable effects on the ErbB receptor isoforms that are recruited and activated. This diversifies dimer formation and subsequent downstream signaling even though the ligands bind to the same receptor (6Beerli R.R. Hynes N.E. J. Biol. Chem. 1996; 271: 6071-6076Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 10Olayioye M.A. Graus-Porta D. Beerli R.R. Rohrer J. Gay B. Hynes N.E. Mol. Cell. Biol. 1998; 18: 5042-5051Crossref PubMed Scopus (220) Google Scholar). Intestinal epithelial cells form a continuous monolayer that lines the intestinal tract. These cells are responsible for the uptake of nutrients, for forming a barrier against pathogens and environmental toxins, and for the tightly regulated absorption and secretion of ions and water. The active secretion of chloride ions provides the driving force for intestinal fluid secretion. The critical importance of regulatory mechanisms governing fluid secretory processes is highlighted by pathological conditions where regulation is impaired. The most dramatic example of excessive chloride and fluid secretion is cholera (11Barrett K.E. Keely S.J. Annu. Rev. Physiol. 2000; 62: 535-572Crossref PubMed Scopus (388) Google Scholar). Complex mechanisms regulate intestinal ion transport, and our laboratory has identified a critical role for the EGFR as a central regulator that limits ion transport stimulated by calcium-dependent agents such as the muscarinic agonist, carbachol (CCh). We have previously shown that the G protein-coupled receptor agonist, CCh, which stimulates chloride secretion across monolayers of T84 colonic epithelial cells, also transactivates the EGFR. This leads in turn to activation of extracellular signal-regulated kinases and a later reduction in the level of chloride secretion (4Keely S.J. Barrett K.E. J. Biol. Chem. 1999; 274: 33449-33454Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 12Keely S.J. Uribe J.M. Barrett K.E. J. Biol. Chem. 1998; 273: 27111-27117Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). Exogenously added EGF can also inhibit CCh-stimulated chloride secretion (4Keely S.J. Barrett K.E. J. Biol. Chem. 1999; 274: 33449-33454Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 13Uribe J.M. Gelbmann C.M. Traynor-Kaplan A.E. Barrett K.E. Am. J. Physiol. 1996; 271: C914-C922Crossref PubMed Google Scholar). The inhibitory effects of CCh-stimulated transactivation versus EGF-dependent activation of the EGFR are, however, attributable to different downstream mechanisms. Divergent signaling evoked by these two stimuli appears to occur at the level of the EGFR, since direct binding of EGF to EGFR causes recruitment of the ErbB2 receptor to form a heterodimer with the EGFR, whereas CCh-stimulated transactivation does not recruit ErbB2 (4Keely S.J. Barrett K.E. J. Biol. Chem. 1999; 274: 33449-33454Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). In addition, the inhibitory effect of EGF on CCh-stimulated Cl– secretion is mediated by activation of PI3K; however, CCh-induced activation of the EGFR does not cause an increase in the lipid kinase activity of PI3K (14Uribe J.M. Keely S.J. Traynor-Kaplan A.E. Barrett K.E. J. Biol. Chem. 1996; 271: 26588-26595Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). We have also shown that CCh transactivation of EGFR is mediated by the extracellular release of TGF-α (15McCole D.F. Keely S.J. Coffey R.J. Barrett K.E. J. Biol. Chem. 2002; 277: 42603-42612Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). This led us to hypothesize that TGF-α and EGF may have different signaling properties in colonic epithelial cells despite both being ligands for EGFR. The aim of this study, therefore, to between and ErbB activation and downstream recruitment the previously signaling between direct and indirect activation of the EGFR by EGF and In we that EGFR to TGF-α and their downstream signaling consequences are by the signaling that in CCh-stimulated transforming growth factor epidermal growth factor EGF receptor and phosphorylation EGFR tyrosine and from the and EGFR used to EGFR, from All other of and monolayers of the T84 colonic cell for of T84 cells in described previously (14Uribe J.M. Keely S.J. Traynor-Kaplan A.E. Barrett K.E. J. Biol. Chem. 1996; 271: 26588-26595Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). T84 cells in with cells cells for on T84 cells are known to the of colonic K. J. Biol. PubMed Scopus Google Scholar). In with the known of their receptors on intestinal CCh, EGF, and TGF-α added in R. J. PubMed Scopus Google Scholar, R.J. 1996; PubMed Scopus Google Scholar). cell monolayers in and in at The composition of the and to by the of these changes in in response to are of chloride secretion K. J. PubMed Scopus Google Scholar). and cell monolayers with for at and then stimulated with and as The by in and in and in for then from the into and at for for protein protein and that an of cell with for at by with protein The in and in by and and by of secondary or of cells at a of cells in the and to phosphatase 1B from and of into T84 cell the as the and for After cells stimulated with CCh, EGF, or for the of A used as are as the for a of or of with the used to as to EGF and TGF-α in of the EGFR and ErbB2 in the set to the EGFR EGF and TGF-α in EGFR phosphorylation in T84 colonic epithelial T84 cells, on with CCh EGF or a of of TGF-α The of CCh or growth factor has previously shown by our to for of EGFR phosphorylation in this S.J. Uribe J.M. Barrett K.E. J. Biol. Chem. 1998; 273: 27111-27117Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). In addition, the of CCh used is and is well as the of calcium-dependent chloride secretion across intestinal epithelial cells by our and J.M. Gelbmann C.M. Traynor-Kaplan A.E. Barrett K.E. Am. J. Physiol. 1996; 271: C914-C922Crossref PubMed Google Scholar, M. C. C. E. C. Am. J. Physiol. 1989; Google Scholar, M. C. Traynor-Kaplan A.E. S.J. Barrett K.E. J. PubMed Scopus Google Scholar). of cell with an and for that CCh and EGF EGFR phosphorylation as EGFR are shown in TGF-α also EGFR phosphorylation in a with being the However, that a of TGF-α to EGFR phosphorylation at to that by EGF This in a set of where T84 cells with CCh TGF-α or a of EGF EGF not at than to the of this with of TGF-α, as shown in EGF EGFR phosphorylation in a EGFR are shown in that EGFR tyrosine phosphorylation stimulated by EGF at with that by a of TGF-α Furthermore, EGF EGFR phosphorylation at whereas the of TGF-α that stimulated EGFR phosphorylation These that EGF is than TGF-α at EGFR phosphorylation in colonic epithelial shown that EGF is a of EGFR activation than TGF-α, we this in also to ErbB2 receptor monolayers of T84 cells with CCh EGF or a of of TGF-α EGF, not CCh, ErbB2 phosphorylation Furthermore, TGF-α to cause ErbB2 phosphorylation at G and of TGF-α that of EGFR phosphorylation not ErbB2 This in by the of a of EGF to ErbB2 phosphorylation in T84 cells for and ErbB2 shown in and EGF ErbB2 phosphorylation at a of versus The level of phosphorylation by EGF at this than that by TGF-α These that EGF is also than TGF-α at ErbB2 TGF-α of Cl– ErbB2 the of our for regulation of chloride secretion. We of chloride secretion by TGF-α activation of the ErbB2 receptor. monolayers of T84 cells in of CCh stimulated a Cl– transport response of CCh-stimulated after with TGF-α at a of This of TGF-α is well the to ErbB2 receptor phosphorylation that ErbB2 is to involved in of Cl– secretion. shown that TGF-α inhibit CCh-stimulated at to the ErbB2 receptor, we set to these findings by ErbB2 activation and effect on the of TGF-α to inhibit secretory to CCh in T84 Our to a of ErbB2 N. A. C. A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). we that TGF-α of ErbB2 a of ErbB2 from cell of cells stimulated with TGF-α with or with or and for ErbB2 phosphorylation at both and no effect on the of TGF-α to EGFR phosphorylation Furthermore, not the of EGF to phosphorylation of the EGFR can TGF-α of ErbB2 we ErbB2 activation is for the inhibitory effect of a of TGF-α on CCh-stimulated cell monolayers in and for with at or or with TGF-α the response to CCh or not These with the in that ErbB2 activation is not for of the chloride secretory response to ErbB2 for of PI3K CCh transactivates the EGFR via the release of TGF-α (15McCole D.F. Keely S.J. Coffey R.J. Barrett K.E. J. Biol. Chem. 2002; 277: 42603-42612Abstract Full Text Full Text PDF PubMed Scopus (99) Google we that the differential of EGF and TGF-α for the of EGF and CCh to recruit different signals downstream of EGFR. We have previously that of calcium-dependent Cl– secretion by exogenous EGF PI3K whereas of Cl– secretion mediated by CCh-stimulated transactivation of the EGFR does not (14Uribe J.M. Keely S.J. Traynor-Kaplan A.E. Barrett K.E. J. Biol. Chem. 1996; 271: 26588-26595Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). to ErbB2 activation for PI3K we of Cl– secretion by exogenous TGF-α, at that not ErbB2, involved PI3K activation. that TGF-α PI3K as by phosphorylation of the PI3K downstream on This effect at TGF-α to ErbB2 A and These that TGF-α can PI3K of The of PI3K in TGF-α of Cl– secretion by that the PI3K and the inhibitory effect of a of TGF-α, on chloride secretion and TGF-α Cl– secretion via PI3K in an in ErbB2 activation not for differential recruitment of PI3K in the regulation of Cl– secretion by direct versus indirect activation of EGFR. of EGFR a of than the signaling between direct versus indirect EGFR activation not mediated at the level of ErbB2 kinase we the for differential recruitment by direct versus indirect EGFR activation at the level of EGFR EGFR activation and recruitment of downstream signaling pathways is on phosphorylation of EGFR tyrosine M.A. Graus-Porta D. Beerli R.R. Rohrer J. Gay B. Hynes N.E. Mol. Cell. Biol. 1998; 18: 5042-5051Crossref PubMed Scopus (220) Google Scholar). EGFR four autophosphorylation and EGFR and are also binding for the which is involved in recruitment of protein kinase pathways R. M. R. D. Ullrich A. J. J. Biol. Chem. 1989; Full Text PDF PubMed Google Scholar, D. J.M. J. Mol. Cell. Biol. PubMed Google Scholar). In addition, we have previously shown that with the EGFR CCh-stimulated transactivation S.J. Uribe J.M. Barrett K.E. J. Biol. Chem. 1998; 273: 27111-27117Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). is a autophosphorylation and also as a binding for D. B. M. Daly R.J. N. Ullrich A. J. EMBO J. PubMed Scopus Google Scholar, C. Mol. Cell. Biol. PubMed Scopus Google Scholar). is by kinase and is in the kinase of EGFR K. A. M. Y. PubMed Scopus Google Scholar). We EGFR tyrosine phosphorylation after with EGF, CCh, or TGF-α to in EGFR tyrosine phosphorylation for differential recruitment of ion transport regulatory pathways by EGF versus T84 monolayers with CCh, EGF, or TGF-α, and on and to with against the of EGFR tyrosine EGF, CCh, and TGF-α phosphorylation of the autophosphorylation and EGF a than TGF-α and However, both EGF and TGF-α phosphorylation of the other autophosphorylation CCh to increase phosphorylation of this of cells with EGF and TGF-α, not CCh, phosphorylation of the other three stimuli phosphorylation of recruitment these that both EGF and TGF-α, with different are of of the EGFR whereas CCh phosphorylation of four of these with no increase in the phosphorylation of EGFR or therefore, CCh some other regulatory that EGFR tyrosine phosphorylation by This for differential activation of PI3K, since both and of EGFR have in activation of this M. J. Mol. Cell. Biol. 2000; PubMed Scopus Google of EGFR tyrosine phosphorylation by at by at in a for Divergent of PI3K by of the of EGFR activation not EGFR tyrosine phosphorylation also of tyrosine by protein-tyrosine to activation. we activity involved in the differential phosphorylation of EGFR and subsequent activation of PI3K by direct (EGF) or indirect activation of EGFR. In the of the phosphorylation of and in response to CCh with CCh or not CCh-induced phosphorylation of the level of phosphorylation by CCh A and However, increase EGFR tyrosine phosphorylation by CCh Our findings with with a distinct phenylarsine also the of CCh to phosphorylation of EGFR A and and EGFR A and with CCh whereas no effect on CCh-stimulated phosphorylation of versus A and also with EGF as a and a reduction in phosphorylation of and with EGF also a level of phosphorylation in response to CCh and that CCh is of PI3K signaling protein-tyrosine phosphatase activity is Moreover, CCh transactivates EGFR by the release of the EGFR ligand, TGF-α, does not of the same EGFR or recruit the same signaling molecules that to exogenous TGF-α, these that direct versus indirect activation of the EGFR may associated with activity of that EGFR phosphatase by phenylarsine phosphorylation of EGFR tyrosine and and activation of PI3K T84 cells with either physiological or for with CCh or EGF from cell with against EGFR and then and for EGFR. of phosphorylation of EGFR and for phosphorylation of the PI3K downstream and of All are as for a of from from with CCh and from EGF of CCh-induced EGFR and and PI3K The tyrosine phosphatase activity in differential EGFR signaling not a is a well of EGFR tyrosine phosphorylation and EGFR activity D. A. 1997; PubMed Scopus Google Scholar, B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, activity can by and J. J. B. M.J. C. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1989; Full Text PDF PubMed Google Scholar). we the EGFR phosphorylation and downstream recruitment in response to CCh interfering used to in T84 A into T84 cells, whereas a of used to for effects of in T84 monolayers with a reduction of no effect on cellular protein as by of the in both and cells as well as EGFR protein as shown in T84 of CCh-induced phosphorylation of on the EGFR whereas T84 cells with no in phosphorylation after CCh Furthermore, the of CCh to phosphorylation of on the EGFR CCh of EGFR phosphorylation and PI3K T84 cell monolayers with or with CCh or EGF for cell by for phosphorylation of EGFR and of phosphorylation of EGFR of as a in and are as the for a of from cells with and from CCh of cells from the same also for PI3K as by activation of the downstream CCh an increase in phosphorylation in cells to whereas cells with no response to CCh These with in and that protein-tyrosine phosphatase for or by PTP1B, CCh-stimulated EGFR transactivation from the of EGFR tyrosine that are by exogenous EGFR transactivation of the EGFR and direct activation of EGFR with its ligand, EGF, both result in of calcium-dependent chloride secretion across intestinal epithelial However, different signaling pathways downstream of the EGFR are recruited by these two of EGFR activation. The these findings to demonstrate that the signaling between direct and indirect activation of EGFR are for by differential effects on protein-tyrosine phosphatase activity. Although EGF and TGF-α bind to the same receptor, is some to that these ligands bind with different the EGFR TGF-α with than EGF R. Ullrich A. D. J. EMBO J. 1989; PubMed Scopus (144) Google Scholar). in EGF versus TGF-α have also described in a number of other cellular R. PubMed Scopus Google Scholar, A.E. De van Vugt M.J. van De Poll M.L. van Zoelen E.J. J. 1998; PubMed Scopus Google Scholar). in may by that EGF and TGF-α bind to different on the extracellular ligand binding of the EGFR. by A.E. De van Vugt M.J. van De Poll M.L. van Zoelen E.J. J. 1998; PubMed Scopus Google that this is by the of EGF and TGF-α, which bind to on EGFR. In addition, M. B. 1989; PubMed Scopus Google an against EGFR, that inhibit TGF-α not EGF binding, that binding of these ligands not In our EGF and TGF-α different for both EGFR and ErbB2 phosphorylation In the study, that ErbB2 activation is not for TGF-α of chloride secretion across colonic epithelial These results are also in with our findings CCh-induced transactivation of the EGFR can inhibit subsequent chloride CCh does not cause ErbB2 recruitment to the EGFR, and CCh stimulates the release of TGF-α at that are than to cause ErbB2 phosphorylation S.J. Uribe J.M. Barrett K.E. J. Biol. Chem. 1998; 273: 27111-27117Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 13Uribe J.M. Gelbmann C.M. Traynor-Kaplan A.E. Barrett K.E. Am. J. Physiol. 1996; 271: C914-C922Crossref PubMed Google Scholar, D.F. Keely S.J. Coffey R.J. Barrett K.E. J. Biol. Chem. 2002; 277: 42603-42612Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). The most of signaling between direct versus indirect EGFR activation and subsequent regulation of epithelial Cl– however, is the differential activation of We that the of TGF-α CCh-stimulated transactivation of the EGFR to ErbB2 and recruit Our however, that exogenous TGF-α of ErbB2 not of CCh-stimulated Cl– secretion also PI3K signaling as by activation of the PI3K downstream In addition, the inhibitory effect of of TGF-α on CCh-stimulated Cl– secretion at in that of exogenous TGF-α PI3K CCh transactivation of the EGFR is this the question as to direct of exogenous EGF or TGF-α a different signaling than indirect activation of the EGFR mediated by We that the in the pattern of phosphorylation of tyrosine on the EGFR involved in receptor activation and we whereas EGF and TGF-α of the tyrosine CCh not or which are binding for and phosphorylation is regulated by the of protein-tyrosine kinases and in the between the of tyrosine and kinases the tyrosine phosphorylation pattern of and have in the of and PubMed Scopus Google Scholar). therefore, our to the of protein-tyrosine which are of in the regulation of EGFR phosphorylation after direct versus indirect EGFR activation. phosphatase the of CCh to and to PI3K protein-tyrosine phosphatase also the of EGF to and that EGF may activation of protein-tyrosine such as S.A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. Mol. Cell. Biol. 2000; PubMed Scopus Google to EGFR tyrosine These that CCh may either or to inhibit the activity of involved in EGFR tyrosine We on D. A. 1997; PubMed Scopus Google as a phosphatase it is the of the family and a tyrosine phosphatase that can regulate signaling by a number of growth factor receptors 2002; PubMed Scopus Google Scholar, Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. PubMed Scopus Google Scholar). Moreover, has shown to have a for on the EGFR D. A. S.J. J. Biol. Chem. Full Text PDF Google Scholar, J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). We that of CCh phosphorylation of and on the EGFR. Moreover, CCh also to PI3K signaling in These our findings with of and a role for these including PTP1B, in differential outcomes of EGFR signaling in response to different of receptor activation. to on the mechanisms involved in regulation and the effects of EGF, TGF-α, and CCh, muscarinic GPCR on activity. in other have that the binding of EGF to the EGFR can mechanisms to phosphatase of J.M. PubMed Scopus Google Scholar, K. Biol. 2002; PubMed Scopus Google Scholar). In this cause EGFR tyrosine in recruitment of signaling pathways that recruited in the of phosphatase This has for conditions where of phosphatase such as are in ErbB signaling and have also in a number of epithelial both from chronic conditions such as E. R. J. 1997; Google Scholar, R. J. 17: PubMed Scopus Google and after activation by such as receptors and receptors D. H. M. Mol. Google Scholar, D. 2002; PubMed Scopus Google Scholar). direct to our EGFR regulation of ion transport and recruitment of ion transport regulatory signaling pathways is with in the of intestinal D.F. N. Barrett K.E. Full Text Full Text PDF PubMed Scopus Google Scholar). The of other protein-tyrosine in our however, as protein-tyrosine with the EGFR M.J. Mol. Cell. Biol. PubMed Scopus Google Scholar, B. J. Biol. PubMed Scopus Google Scholar). A of this differential signaling and its role in the regulation of epithelial chloride secretion is shown in In the central role of EGFR in the regulation of cell and its in a number of such as epithelial dictates that EGFR signaling tightly regulated in response to different EGFR has shown to by and a variety of peptide EGFR acts as a central for and the molecules involved in both appropriate and of the of information from the extracellular are critical to cell We have a role for one such the EGFR PTP1B, in the regulation of epithelial chloride secretion. Furthermore, we have that phosphatase activity governs the differential recruitment of signaling pathways by direct versus indirect activation of the EGFR. in to our of via the EGFR, these findings may also a in conditions by growth factor