Fibroblast Growth Factor-2-induced Signaling through Lipid Raft-associated Fibroblast Growth Factor Receptor Substrate 2 (FRS2)

The plasma membrane is not homogenous but contains specific subcompartments characterized by their unique lipid and protein composition. Based on their enrichment in various signaling molecules, these membrane microdomains are recognized to be sites of localized signal transduction for a number of extracellular stimuli. We have previously shown that fibroblast growth factor-2 (FGF2) induced a specific signaling response within a lipid raft membrane microdomain in human neuroblastoma cells characterized by the tyrosine phosphorylation of a p80 phosphoprotein. Herein, we show that this protein is the signaling adaptor FRS2 and that it is localized exclusively to lipid rafts in vitro and in vivo. We have examined how the tyrosine phosphorylation and serine-threonine phosphorylation of FRS2 within lipid rafts affect the response of cells to FGF2 signaling. Our data suggest that activation of protein kinase C, Src family kinases, and MEK1/2 are involved in regulating serine-threonine phosphorylation of FRS2, which can indirectly affect FRS2 phosphotyrosine levels. We also show that Grb2 is recruited to lipid rafts during signaling events and that activation of MEK1/2 by different mechanisms within lipid rafts may lead to different cellular responses. This work suggests that compartmentalized signaling within lipid rafts may provide a level of specificity for growth factor signaling. The plasma membrane is not homogenous but contains specific subcompartments characterized by their unique lipid and protein composition. Based on their enrichment in various signaling molecules, these membrane microdomains are recognized to be sites of localized signal transduction for a number of extracellular stimuli. We have previously shown that fibroblast growth factor-2 (FGF2) induced a specific signaling response within a lipid raft membrane microdomain in human neuroblastoma cells characterized by the tyrosine phosphorylation of a p80 phosphoprotein. Herein, we show that this protein is the signaling adaptor FRS2 and that it is localized exclusively to lipid rafts in vitro and in vivo. We have examined how the tyrosine phosphorylation and serine-threonine phosphorylation of FRS2 within lipid rafts affect the response of cells to FGF2 signaling. Our data suggest that activation of protein kinase C, Src family kinases, and MEK1/2 are involved in regulating serine-threonine phosphorylation of FRS2, which can indirectly affect FRS2 phosphotyrosine levels. We also show that Grb2 is recruited to lipid rafts during signaling events and that activation of MEK1/2 by different mechanisms within lipid rafts may lead to different cellular responses. This work suggests that compartmentalized signaling within lipid rafts may provide a level of specificity for growth factor signaling. Fibroblast growth factors (FGFs) 1The abbreviations used are: FGFfibroblast growth factorFGFRFGF receptorSHSrc homologyPKCprotein kinase CTPA12-O-tetradecanoylphorbol-13-acetateBisbisindolylmaleimideFRS2fibroblast growth factor receptor substrate 2PKCprotein kinase CERKextracellular signal-regulated kinaseMAPKmitogen-activated protein kinaseMEKmitogen-activated protein kinase/extracellular signal-regulated kinase kinase constitute a large family of peptide hormones that influence a wide variety of biological processes such as angiogenesis, embryogenesis, differentiation, and proliferation depending on the cell type (1Basilico C. Moscatelli D. Adv. Cancer Res. 1992; 59: 115-165Crossref PubMed Scopus (1053) Google Scholar, 2Galzie Z. Kinsella A.R. Smith J.A. Biochem. Cell Biol. 1997; 75: 669-685Crossref PubMed Scopus (183) Google Scholar). In the nervous system, FGFs have been shown to stimulate both the differentiation and survival of post-mitotic cells as well as being proliferative factors for non-differentiated cells (3Gritti A. Parati E.A. Cova L. Frolischthal P. Galli R. Wanke E. Favarelli L. Morassutti D.J. Roisen F. Nickel D.D. Vescovi A.L. J. Neurosci. 1996; 16: 1091-1100Crossref PubMed Google Scholar). FGFs induce their biological effects by binding to and activating a family of trans-membrane receptor tyrosine kinases (FGFR1–4) (2Galzie Z. Kinsella A.R. Smith J.A. Biochem. Cell Biol. 1997; 75: 669-685Crossref PubMed Scopus (183) Google Scholar, 4Jaye M. Schlessinger J. Dionne C.A. Biochim. Biophys. Acta. 1992; 1135: 185-199Crossref PubMed Scopus (597) Google Scholar). The activation of the FGFRs occurs by dimerization of the trans-membrane receptors upon the binding of the FGF ligand followed by autophosphorylation of a number of tyrosine residues, some of which can act as recruitment sites for various downstream effectors (2Galzie Z. Kinsella A.R. Smith J.A. Biochem. Cell Biol. 1997; 75: 669-685Crossref PubMed Scopus (183) Google Scholar, 4Jaye M. Schlessinger J. Dionne C.A. Biochim. Biophys. Acta. 1992; 1135: 185-199Crossref PubMed Scopus (597) Google Scholar, 5Schlessinger J. Ullrich A. Neuron. 1992; 9: 383-391Abstract Full Text PDF PubMed Scopus (1292) Google Scholar, 6Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4611) Google Scholar). fibroblast growth factor FGF receptor Src homology protein kinase C 12-O-tetradecanoylphorbol-13-acetate bisindolylmaleimide fibroblast growth factor receptor substrate 2 protein kinase C extracellular signal-regulated kinase mitogen-activated protein kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase One relatively unique aspect of FGF signaling is the recruitment of signaling molecules to FGFRs through the adaptor protein FGF receptor substrate 2 (FRS2, a.k.a. Suc1-associated neurotrophic factor target or SNT) (7Kouhara H. Hadari Y.R. Spivak-Kroizman T. Schilling J. Bar-Sagi D. Lax I. Schlessinger J. Cell. 1997; 89: 693-702Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar, 8Rabin S.J. Cleghon V. Kaplan D.R. Mol. Cell. Biol. 1993; 13: 2203-2213Crossref PubMed Scopus (174) Google Scholar). FRS2 associates directly with FGFRs and shows increased tyrosine phosphorylation upon FGFR signaling and functions to recruit SH2 domain-containing proteins such as Grb2 that link the FGFR to a variety of downstream pathways (7Kouhara H. Hadari Y.R. Spivak-Kroizman T. Schilling J. Bar-Sagi D. Lax I. Schlessinger J. Cell. 1997; 89: 693-702Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar, 9Goh K.C. Lim Y.P. Ong S.H. Siak C.B. Cao X. Tan Y.H. Guy G.R. J. Biol. Chem. 1996; 271: 5832-5838Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 10Wang J.-K. Xu H. Li H.-C. Goldfarb M. Oncogene. 1996; 13: 721-729PubMed Google Scholar). FRS2 also exhibits a high level of serine-threonine as well as tyrosine phosphorylation (7Kouhara H. Hadari Y.R. Spivak-Kroizman T. Schilling J. Bar-Sagi D. Lax I. Schlessinger J. Cell. 1997; 89: 693-702Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar, 10Wang J.-K. Xu H. Li H.-C. Goldfarb M. Oncogene. 1996; 13: 721-729PubMed Google Scholar). The function of the serine-threonine phosphorylation on FRS2 is presently unclear, although it may provide another level of specificity to the FGFR signaling by regulating pathways distinct from those associated with the tyrosine phosphorylation of FRS2. The importance of FRS2 in FGF signaling is reflected in the embryonic lethal phenotype observed during mouse development after disruption of theFRS2 gene. In addition, FRS2 null cell lines derived from these embryos show an impairment of FGF-induced migration, proliferation, and MAPK activation (11Hadari Y.R. Gotoh N. Kouhara H. Lax I. Schlessinger J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8578-8583Crossref PubMed Scopus (241) Google Scholar). FGFR signaling also leads to activation of members of the Src protein tyrosine kinase family (12Kuo W.-L. Chung K.-C. Rosner M.R. Mol. Cell. Biol. 1997; 17: 4633-4643Crossref PubMed Scopus (78) Google Scholar). Studies on Xenopus laevis have demonstrated that Laloo, a novel member of the Src family of tyrosine kinases, is required for mesoderm induction in response to FGF (13Weinstein D.C. Marden J. Carnevali F. Hemmati-Brivanlou A. Nature. 1998; 394: 904-908Crossref PubMed Scopus (74) Google Scholar). The cooperation of FRS2 and Laloo in this pathway is suggested by the observed association of FRS2 with Laloo (14Kusakabe M. Masuyama N. Hanafusa H. Nishida E. EMBO Rep. 2001; 2: 727-735Crossref PubMed Scopus (24) Google Scholar,15Hama J. Suri C. Haremaki T. Weinstein D.C. J. Biol. Chem. 2002; 277: 19806-19810Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar). Although many receptor tyrosine kinases activate similar downstream pathways such as the MAPK pathway, they induce specific phenotypic responses from the cell. Specificity can be achieved temporally by the developmentally regulated expression of certain components of the pathways. For instance, the expression of different FGFR types is regulated during oligodendrocyte maturation, providing a molecular basis for the developmentally varying response of cells to a common ligand (16Bansal R. Kumar M. Murray K. Morrison R.S. Pfeiffer S.E. Mol. Cell. Neurosci. 1996; 7: 263-275Crossref PubMed Scopus (143) Google Scholar). Specificity can also originate from the type of receptor expressed, because all of the FGFRs do not appear to have the same efficiency at activating various downstream pathways (17Lin H.Y. Xu J. Ischenko I. Ornitz D.M. Halegoua S. Hayman M.J. Mol. Cell. Biol. 1998; 18: 3762-3770Crossref PubMed Scopus (60) Google Scholar, 18Ornitz D.M. Xu J. Colvin J.S. McEwen D.G. MacArthur C.A. Coulier F. Gao G. Goldfarb M. J. Biol. Chem. 1996; 271: 1592-15297Abstract Full Text Full Text PDF Scopus (1423) Google Scholar, 19Wang J.-K. Gao G. Goldfarb M. Mol. Cell. Biol. 1994; 14: 181-188Crossref PubMed Scopus (206) Google Scholar). In addition, the location of the receptor or downstream events within the cell may add another level of specificity in the signaling response. Microdomains within the plasma membrane such as lipid rafts function to sequester signaling molecules and act as sites of signal transduction that can regulate cell physiology (20Anderson R.G.W. Annu. Rev. Biochem. 1998; 67: 199-225Crossref PubMed Scopus (1725) Google Scholar, 21Schlegel A. Volonte D. Engelman J.A. Galbiati F. Mehta P. Zhang X.-L. Scherer P.E. Lisanti M.P. Cell. Signalling. 1998; 10: 457-463Crossref PubMed Scopus (153) Google Scholar, 22Simons K. Ikonen E. Nature. 1997; 387: 569-572Crossref PubMed Scopus (8117) Google Scholar). Lipid rafts are characterized by their enrichment in glycosphingolipids and cholesterol as well as by their unique protein composition (20Anderson R.G.W. Annu. Rev. Biochem. 1998; 67: 199-225Crossref PubMed Scopus (1725) Google Scholar, 22Simons K. Ikonen E. Nature. 1997; 387: 569-572Crossref PubMed Scopus (8117) Google Scholar). On the inner leaflet of the plasma membrane, proteins such as G-proteins and members of the Src-family of protein tyrosine kinases are found associated with these membrane microdomains (23Robbins S.M. Quintrell N.A. Bishop J.M. Mol. Cell. Biol. 1995; 15: 3507-3515Crossref PubMed Scopus (229) Google Scholar, 24Sargiacomo M. Sudol M. Z. Lisanti M.P. J. Cell Biol. 1993; PubMed Scopus Google Scholar, D.J. J. D.C. D.M. J. Cell Biol. 1994; PubMed Scopus Google Scholar). are at different that can be by their and protein composition K. Ikonen E. Nature. 1997; 387: 569-572Crossref PubMed Scopus (8117) Google Scholar). are such characterized by the of a protein as the of these E. K. Proc. Natl. Acad. Sci. U. S. A. 1995; PubMed Scopus Google Scholar, C. R. V. S. L. E. C. J. Cell Biol. 1998; PubMed Scopus Google Scholar, S. R. F. J. A. T. Mol. Biol. Cell. 1995; PubMed Scopus Google Scholar, R.G.W. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar). to function in R.G.W. 1992; PubMed Scopus Google Scholar). their functions are to events such as an of receptor of a of of and a localized for signal transduction (20Anderson R.G.W. Annu. Rev. Biochem. 1998; 67: 199-225Crossref PubMed Scopus (1725) Google Scholar, R.G.W. 1992; PubMed Scopus Google Scholar, R.G.W. Cell Biol. 1993; PubMed Scopus Google Scholar, T. J. Cell Biol. 1993; PubMed Scopus Google Scholar, T. S. A. K. K. J. Cell Biol. 1992; PubMed Scopus Google Scholar, and Scholar). we observed an signaling that localized to membrane microdomains that we A. C. S.M. J. PubMed Scopus Google Scholar). Herein, we have the protein FRS2 as a lipid both in vitro and in the mouse We have also examined FGF2 signaling through FRS2 within lipid rafts and show that serine-threonine phosphorylation of FRS2 is on a pathway protein kinase C Src family kinases, and MEK1/2 and that FGF2 signaling through MEK1/2 may have different phenotypic in the cell depending upon the pathway used for activation of from and from from MAPK from and from cells in with and at in to growth factor cells in with for with 12-O-tetradecanoylphorbol-13-acetate or for the in with the of or bisindolylmaleimide or or to the cells for to cell with and in and of and by at for at with FRS2 for at and the for an at The with and the in to on the proteins to and in and and for for with a of the in their The in and or and This followed by for with in The as and an to on and as in and in The cells on and and as in previously (23Robbins S.M. Quintrell N.A. Bishop J.M. Mol. Cell. Biol. 1995; 15: 3507-3515Crossref PubMed Scopus (229) Google Scholar). mouse embryos at and and in on and of as work from shown that FGF2 unique from growth factors growth factor and growth and in that it to induce a compartmentalized signaling response in a human neuroblastoma cell A. C. S.M. J. PubMed Scopus Google Scholar). In we to these membrane microdomains as because the cells both and we have characterized this membrane on and it is to to these as lipid with S.M. J. Biochem. 2002; PubMed Scopus Google Scholar). We observed that FGF2 to induce an in tyrosine phosphorylation of proteins within the lipid raft an protein that to proteins or A. C. S.M. J. PubMed Scopus Google Scholar). with or SH2 is a of the adaptor FRS2, and family members (7Kouhara H. Hadari Y.R. Spivak-Kroizman T. Schilling J. Bar-Sagi D. Lax I. Schlessinger J. Cell. 1997; 89: 693-702Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar, 8Rabin S.J. Cleghon V. Kaplan D.R. Mol. Cell. Biol. 1993; 13: 2203-2213Crossref PubMed Scopus (174) Google Scholar, 10Wang J.-K. Xu H. Li H.-C. Goldfarb M. Oncogene. 1996; 13: 721-729PubMed Google Scholar). in an to and the we used to FRS2 to cell that been with FGF2 for that FRS2 is localized exclusively to lipid raft and with the phosphotyrosine at in the lipid raft also observed in the and for FRS2 This observed to be in response to it is a or a FGF of FRS2 from cell that the FRS2 in response to FGF2 we have FRS2 as a protein that is localized to the lipid raft of that this not unique to cell we also examined the expression and of FRS2 at various in the mouse mouse on and by for FRS2 We found that FRS2 at of the of development examined and that in all FRS2 localized to the lipid raft The FRS2 response to FGF2 is characterized by an increased tyrosine phosphorylation as well as a in on that been to the of serine-threonine kinases FRS2 J.-K. Xu H. Li H.-C. Goldfarb M. Oncogene. 1996; 13: 721-729PubMed Google Scholar). we have used the as an of FRS2 serine-threonine levels. FGFRs have been shown to activate M. D. R. F. Li Dionne C.A. M. M. Schlessinger J. Mol. Cell. Biol. PubMed Google which can lead to the activation of we examined the that involved in serine-threonine phosphorylation of FRS2. a of we the in of FRS2, of serine-threonine phosphorylation The effects of FGF2 on FRS2 be by an of the Src family kinases, or the that and Src family kinase are required for serine-threonine phosphorylation of FRS2 serine-threonine phosphorylation of FRS2 also by the MEK1/2 that activation of the MAPK is also required for serine-threonine phosphorylation of FRS2. The in in FRS2 FGF2 be a that and novel as well as cells with which of not E. A. M. A. Biochem. J. 1996; PubMed Scopus Google Scholar). The of FRS2 induced by also be in the of or data that activation of lead to serine-threonine phosphorylation of FRS2 and that it also on downstream activation of Src family kinases and MEK1/2 as observed for FGF2 FRS2 in lipid raft and not in the of the cells of phosphotyrosine in lipid rafts that FGF2 induced tyrosine phosphorylation of FRS2, which not by of the cells with or that serine-threonine phosphorylation of these tyrosine phosphorylation of FRS2 to be of the cells with not in the increased tyrosine phosphorylation of FRS2 suggest that serine-threonine phosphorylation of FRS2 is not required for tyrosine phosphorylation of FRS2 to and that the serine-threonine phosphorylation of FRS2 can lead to tyrosine FRS2 been shown to directly recruit Grb2 and activate the MAPK pathway in response to FGF2 S.H. K.C. Lim Y.P. P. L. Cao X. Tan Y.H. Guy G.R. Biochem. Biophys. Res. 1996; PubMed Scopus Google Scholar, H. Goldfarb M. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). We also that Grb2 associates in a with FRS2 in cells as by of FRS2 not FRS2 associated exclusively with lipid we examined the level of Grb2 recruitment to lipid rafts after cell Grb2 in the cell all of the examined Grb2 not in lipid rafts or at levels. FGF2 induced the recruitment of Grb2 to lipid and this not by or which serine-threonine phosphorylation of FRS2. observed for tyrosine phosphorylation of FRS2, it that Grb2 recruitment to lipid rafts that serine-threonine phosphorylation of FRS2 not induce Grb2 recruitment to lipid although some Grb2 after in the of data suggest that serine-threonine phosphorylation of FRS2 is for the recruitment of Grb2 to lipid tyrosine phosphorylation of FRS2 Grb2 to lipid of the lipid raft by for protein which be involved in FRS2 we at the expression of in cells to to lipid raft in the that lipid raft although the of not appear to be by FGF2 the from lipid rafts and not in not that may be the involved in signaling through FRS2 in We have shown that Grb2 is recruited to FRS2 in lipid rafts in the of FRS2 serine-threonine We examined the serine-threonine phosphorylation of FRS2 downstream MAPK the of cells with FGF2 for FRS2 and examined by for a in various the Src family kinase or the family we observed an of the in of FRS2 induced by FGF2 The effects of and not observed the or used observed the tyrosine phosphorylation of an in the tyrosine FRS2 at that to the of FRS2 in the cell from cells with the same used to the phosphorylation of found that FGF2 and that MAPK activation by FGF2 data suggest that MAPK activation with FRS2 tyrosine serine-threonine phosphorylation of FRS2 is not required for the of that lead to MAPK cells that with FGF2 for a from a to a This in not the cells with or for the same the cells with the the cell and the cells in a In the of the cells with the to the cell these suggest that FGF2 to induce cell through a pathway and that this pathway not the activation of In we have shown that FRS2 is a lipid both in the cell used and vivo. We have also shown that FGF2 signaling through FRS2 pathways that appear to regulate distinct phenotypic responses in the cell. FRS2 as an adaptor protein involved in FGF signaling that at the with the of a (7Kouhara H. Hadari Y.R. Spivak-Kroizman T. Schilling J. Bar-Sagi D. Lax I. Schlessinger J. Cell. 1997; 89: 693-702Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar). The functions to target FRS2 to the membrane, and (7Kouhara H. Hadari Y.R. Spivak-Kroizman T. Schilling J. Bar-Sagi D. Lax I. Schlessinger J. Cell. 1997; 89: 693-702Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar, S.H. K.C. Lim Y.P. P. L. Cao X. Tan Y.H. Guy G.R. Biochem. Biophys. Res. 1996; PubMed Scopus Google have shown that FRS2 is localized to the membrane of cells and that membrane association is required for signaling to through FRS2. we have shown that FRS2 is not to the plasma membrane but that it is localized to lipid rafts within the membrane, both in cells and also in lipid rafts from various of mouse signaling molecules have been to be within lipid and membrane microdomains are to act as for regulated of signal transduction that influence downstream signaling from a variety of membrane receptors K. Ikonen E. Nature. 1997; 387: 569-572Crossref PubMed Scopus (8117) Google Scholar). The of FRS2 to lipid rafts is in regulating with molecules such as FRS2 with FGFR to the association of the proteins that been demonstrated to the of FGFR and the phosphotyrosine binding of FRS2 H. Goldfarb M. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). FRS2 is to be in the nervous K. C. J.M. 2001; PubMed Scopus Google Scholar). Our that FRS2 is also localized to lipid rafts in mouse that this may be for signaling through during We have been to of the FGFRs are localized to lipid rafts A. C. S.M. J. PubMed Scopus Google because of the that the receptors are from the lipid raft the used as been for the growth factor receptor C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). FRS2 contains tyrosine that have been shown to be in response to growth factor signaling (7Kouhara H. Hadari Y.R. Spivak-Kroizman T. Schilling J. Bar-Sagi D. Lax I. Schlessinger J. Cell. 1997; 89: 693-702Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar, 8Rabin S.J. Cleghon V. Kaplan D.R. Mol. Cell. Biol. 1993; 13: 2203-2213Crossref PubMed Scopus (174) Google Scholar). The tyrosine phosphorylation of FRS2 is in signal and been shown to be required for association with Grb2 and downstream activation of the MAPK pathway S.H. K.C. Lim Y.P. P. L. Cao X. Tan Y.H. Guy G.R. Biochem. Biophys. Res. 1996; PubMed Scopus Google Scholar, H. Goldfarb M. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google as well as in the recruitment of signaling molecules such as A. Li A. Schlessinger J. Lax I. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google and S.H. Hadari Y.R. Gotoh N. Guy G.R. Schlessinger J. Lax I. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: PubMed Scopus Google Scholar). it also been shown that the of phosphorylation on FRS2 is on and tyrosine (7Kouhara H. Hadari Y.R. Spivak-Kroizman T. Schilling J. Bar-Sagi D. Lax I. Schlessinger J. Cell. 1997; 89: 693-702Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar, 10Wang J.-K. Xu H. Li H.-C. Goldfarb M. Oncogene. 1996; 13: 721-729PubMed Google Scholar). of the molecular of FRS2 have because of the in that is associated with serine-threonine kinase FRS2 J.-K. Xu H. Li H.-C. Goldfarb M. Oncogene. 1996; 13: 721-729PubMed Google Scholar). In this we have examined the tyrosine and serine-threonine of FRS2 various to the they have on FRS2 signaling within lipid previously been shown that associates directly with the FGFR through SH2 and is involved in FGF signaling M. D. R. F. Li Dionne C.A. M. M. Schlessinger J. Mol. Cell. Biol. PubMed Google Scholar). C is an of we examined the that involved in the serine-threonine phosphorylation of FRS2. been that FRS2 associates with the although it not found to be a substrate of in vitro Y.P. Lim J. Guy G.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Our data suggest that a is involved in the phosphorylation of FRS2, although in with FRS2 may not be a substrate of because we observed an of serine-threonine phosphorylation of FRS2 by both and a for Src family kinase and MEK1/2 downstream of can with Src family kinases through adaptor and tyrosine phosphorylation of been in the of downstream signaling D. D. Oncogene. 2001; PubMed Scopus Google Scholar, I. G. S.H. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the we have shown that the is in lipid the is from lipid rafts from The not not it is that is the involved in or phosphorylation of FRS2 in the of this it been demonstrated that the activation of MAPK in phosphorylation of FRS2, which to regulate the tyrosine signaling through FRS2 I. A. A. A. J. Schlessinger J. Mol. Cell. 2002; 10: Full Text Full Text PDF PubMed Scopus Google Scholar). We also observed that the of serine-threonine phosphorylation of FRS2 leads to increased tyrosine phosphorylation of FRS2 as well as a in the level of Grb2 recruited to lipid rafts that suggests a of FRS2 phosphotyrosine by serine-threonine Although Lax I. A. A. A. J. Schlessinger J. Mol. Cell. 2002; 10: Full Text Full Text PDF PubMed Scopus Google not to be required for the serine-threonine phosphorylation of FRS2 to we have shown that is involved in serine-threonine phosphorylation of FRS2 in through activation of FGF and have been shown to activate the signaling in a M. J.M. D. D. Biochem. Biophys. Res. 2002; PubMed Scopus Google and it is that activation of in response to FGF2 is by certain cell types or certain Our data also suggest a for the activation of MEK1/2 in both and serine-threonine phosphorylation of FRS2. FGF2 Grb2 to lipid rafts and cell in a This suggest that both FGF2 and activating a pathway, the MEK1/2 leads to cell The data suggest that FGF2 may activate MEK1/2 through the recruitment of Grb2 to FRS2 and also by activation of by The activation of MEK1/2 through these different mechanisms may lead to different downstream responses in the cell as been in cell types activation of different of lead to of MAPK within the to different cellular responses A. A. S.M. Oncogene. 2001; PubMed Scopus Google Scholar). FRS2 signaling pathways is shown in In to a of signaling molecules been shown to lipid rafts for various of their signaling mechanisms S.M. J. Biochem. 2002; PubMed Scopus Google Scholar). We have previously shown that the are also to induce a compartmentalized signaling response within the lipid rafts of cells is the for signaling the phosphorylation of a A. C. S.M. J. PubMed Scopus Google this protein is not FRS2. M. S. and S. M. is specificity of signaling within lipid rafts through the recruitment of different signaling molecules to distinct signaling pathways In we have shown that the adaptor protein FRS2 is localized exclusively to lipid rafts within the cell membrane and that this is an factor in the of signaling FRS2 through the of signaling molecules that regulate the phosphorylation of FRS2 or are to FRS2 phosphorylation levels. We have also shown that MEK1/2 is involved in signaling pathways within lipid rafts and that the activation of MEK1/2 through different mechanisms may lead to different cellular responses. We the members of the for their and during the of this We also for during the of this

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.