{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:17:03Z","timestamp":1779344223591,"version":"3.51.4"},"reference-count":47,"publisher":"Proceedings of the National Academy of Sciences","issue":"11","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,5,22]]},"abstract":"<jats:p>The docking protein FRS2 is a major downstream effector that links\n fibroblast growth factor (FGF) and nerve growth factor receptors with\n the Ras\/mitogen-activated protein kinase signaling cascade. In this\n report, we demonstrate that FRS2 also plays a pivotal role in\n FGF-induced recruitment and activation of phosphatidylinositol 3-kinase\n (PI3-kinase). We demonstrate that tyrosine phosphorylation of FRS2\u03b1\n leads to Grb2-mediated complex formation with the docking protein Gab1\n and its tyrosine phosphorylation, resulting in the recruitment and\n activation of PI3-kinase. Furthermore, Grb2 bound to\n tyrosine-phosphorylated FRS2 through its SH2 domain interacts primarily\n via its carboxyl-terminal SH3 domain with a proline-rich region in Gab1\n and via its amino-terminal SH3 domain with the nucleotide exchange\n factor Sos1. Assembly of FRS2\u03b1:Grb2:Gab1 complex induced by FGF\n stimulation results in activation of PI3-kinase and downstream effector\n proteins such as the S\/T kinase Akt, whose cellular localization and\n activity are regulated by products of PI3-kinase. These experiments\n reveal a unique mechanism for generation of signal diversity by growth\n factor-induced coordinated assembly of a multidocking protein complex\n that can activate the Ras\/mitogen-activated protein kinase cascade to\n induce cell proliferation and differentiation, and PI3-kinase to\n activate a mediator of a cell survival pathway.<\/jats:p>","DOI":"10.1073\/pnas.111114298","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T14:44:19Z","timestamp":1027694659000},"page":"6074-6079","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":260,"title":["Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins"],"prefix":"10.1073","volume":"98","author":[{"given":"S. H.","family":"Ong","sequence":"first","affiliation":[{"name":"Department of Pharmacology and The Skirball\r Institute, New York University, Medical School, New York, NY 10016; and\r Institute of Molecular and Cell Biology, 30 Medical Drive,\r Singapore 117609"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y. R.","family":"Hadari","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and The Skirball\r Institute, New York University, Medical School, New York, NY 10016; and\r Institute of Molecular and Cell Biology, 30 Medical Drive,\r Singapore 117609"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Gotoh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and The Skirball\r Institute, New York University, Medical School, New York, NY 10016; and\r Institute of Molecular and Cell Biology, 30 Medical Drive,\r Singapore 117609"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. R.","family":"Guy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and The Skirball\r Institute, New York University, Medical School, New York, NY 10016; and\r Institute of Molecular and Cell Biology, 30 Medical Drive,\r Singapore 117609"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Schlessinger","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and The Skirball\r Institute, New York University, Medical School, New York, NY 10016; and\r Institute of Molecular and Cell Biology, 30 Medical Drive,\r Singapore 117609"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I.","family":"Lax","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and The Skirball\r Institute, New York University, Medical School, New York, NY 10016; and\r Institute of Molecular and Cell Biology, 30 Medical Drive,\r Singapore 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