Critical Role for the Docking-Protein FRS2α in FGF Receptor-Mediated Signal Transduction Pathways
The docking protein FRS2α has been implicated as a mediator of signaling via fibroblast growth factor receptors (FGFRs). We have demonstrated that targeted disruption of FRS2α gene causes severe impairment in mouse development resulting in embryonal lethality at E7.0-E7.5. Experiments with FRS2α-def...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2001-07, Vol.98 (15), p.8578-8583 |
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| creator | Hadari, Y R Gotoh, N Kouhara, H Lax, I Schlessinger, J |
| description | The docking protein FRS2α has been implicated as a mediator of signaling via fibroblast growth factor receptors (FGFRs). We have demonstrated that targeted disruption of FRS2α gene causes severe impairment in mouse development resulting in embryonal lethality at E7.0-E7.5. Experiments with FRS2α-deficient fibroblasts demonstrate that FRS2α plays a critical role in FGF-induced mitogen-activated protein (MAP) kinase stimulation, phosphatidylinositol-3 (PI-3) kinase activation, chemotactic response, and cell proliferation. Following FGF stimulation, tyrosine phosphorylated FRS2α functions as a site for coordinated assembly of a multiprotein complex that includes Gab1 and the effector proteins that are recruited by this docking protein. Furthermore, we demonstrate that different tyrosine phosphorylation sites on FRS2α are responsible for mediating different FGF-induced biological responses. These experiments establish the central role of FRS2α in signaling via FGFRs and demonstrate that FRS2α mediates multiple FGFR-dependent signaling pathways critical for embryonic development. |
| doi_str_mv | 10.1073/pnas.161259898 |
| format | Article |
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We have demonstrated that targeted disruption of FRS2α gene causes severe impairment in mouse development resulting in embryonal lethality at E7.0-E7.5. Experiments with FRS2α-deficient fibroblasts demonstrate that FRS2α plays a critical role in FGF-induced mitogen-activated protein (MAP) kinase stimulation, phosphatidylinositol-3 (PI-3) kinase activation, chemotactic response, and cell proliferation. Following FGF stimulation, tyrosine phosphorylated FRS2α functions as a site for coordinated assembly of a multiprotein complex that includes Gab1 and the effector proteins that are recruited by this docking protein. Furthermore, we demonstrate that different tyrosine phosphorylation sites on FRS2α are responsible for mediating different FGF-induced biological responses. These experiments establish the central role of FRS2α in signaling via FGFRs and demonstrate that FRS2α mediates multiple FGFR-dependent signaling pathways critical for embryonic development.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.161259898</identifier><identifier>PMID: 11447289</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adaptor Proteins, Signal Transducing ; Animals ; Antibodies ; Binding sites ; Biological Sciences ; Cell Division ; Cell growth ; Cell Line ; Cell lines ; Cell Movement ; Complementary DNA ; Delta cells ; Embryos ; Fibroblast Growth Factor 1 ; Fibroblast Growth Factor 2 - metabolism ; Fibroblasts ; FRS2^a protein ; Gab1 protein ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Membrane Proteins - physiology ; Mice ; Mitogen-Activated Protein Kinases - metabolism ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Phosphoproteins - physiology ; Phosphorylation ; Polymerase chain reaction ; Receptors, Fibroblast Growth Factor - metabolism ; Signal Transduction</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2001-07, Vol.98 (15), p.8578-8583</ispartof><rights>Copyright 1993-2001 National Academy of Sciences of the United States of America</rights><rights>Copyright © 2001, The National Academy of Sciences 2001</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c491t-e5333c1139ab3a35b06d2cc8107d848b86e10af5b830d819597dd33b2256183f3</citedby><cites>FETCH-LOGICAL-c491t-e5333c1139ab3a35b06d2cc8107d848b86e10af5b830d819597dd33b2256183f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/98/15.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3056211$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3056211$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11447289$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hadari, Y R</creatorcontrib><creatorcontrib>Gotoh, N</creatorcontrib><creatorcontrib>Kouhara, H</creatorcontrib><creatorcontrib>Lax, I</creatorcontrib><creatorcontrib>Schlessinger, J</creatorcontrib><title>Critical Role for the Docking-Protein FRS2α in FGF Receptor-Mediated Signal Transduction Pathways</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The docking protein FRS2α has been implicated as a mediator of signaling via fibroblast growth factor receptors (FGFRs). We have demonstrated that targeted disruption of FRS2α gene causes severe impairment in mouse development resulting in embryonal lethality at E7.0-E7.5. Experiments with FRS2α-deficient fibroblasts demonstrate that FRS2α plays a critical role in FGF-induced mitogen-activated protein (MAP) kinase stimulation, phosphatidylinositol-3 (PI-3) kinase activation, chemotactic response, and cell proliferation. Following FGF stimulation, tyrosine phosphorylated FRS2α functions as a site for coordinated assembly of a multiprotein complex that includes Gab1 and the effector proteins that are recruited by this docking protein. Furthermore, we demonstrate that different tyrosine phosphorylation sites on FRS2α are responsible for mediating different FGF-induced biological responses. These experiments establish the central role of FRS2α in signaling via FGFRs and demonstrate that FRS2α mediates multiple FGFR-dependent signaling pathways critical for embryonic development.</description><subject>Adaptor Proteins, Signal Transducing</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Binding sites</subject><subject>Biological Sciences</subject><subject>Cell Division</subject><subject>Cell growth</subject><subject>Cell Line</subject><subject>Cell lines</subject><subject>Cell Movement</subject><subject>Complementary DNA</subject><subject>Delta cells</subject><subject>Embryos</subject><subject>Fibroblast Growth Factor 1</subject><subject>Fibroblast Growth Factor 2 - metabolism</subject><subject>Fibroblasts</subject><subject>FRS2^a protein</subject><subject>Gab1 protein</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Membrane Proteins - physiology</subject><subject>Mice</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphoproteins - physiology</subject><subject>Phosphorylation</subject><subject>Polymerase chain reaction</subject><subject>Receptors, Fibroblast Growth Factor - metabolism</subject><subject>Signal Transduction</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1uEzEURi0EoqGwZYXQrMpqUv_O2BIblJKCVNQqLWvLY3sSl4kdbA_Qx-JFeCYcEkLZwMqW7vmu_ekA8BzBKYItOd14laaoQZgJLvgDMEFQoLqhAj4EEwhxW3OK6RF4ktIthFAwDh-DI4QobTEXE9DNostOq6FahMFWfYhVXtnqLOhPzi_rqxiydb6aL67xj-_V9nY-rxZW200Osf5gjVPZmuraLX3ZcROVT2bU2QVfXam8-qru0lPwqFdDss_25zH4OH97M3tXX1yev5-9uag1FSjXlhFCNEJEqI4owjrYGKw1LzUNp7zjjUVQ9azjBBqOBBOtMYR0GLMGcdKTY_B6t3czdmtrtPU5qkFuolureCeDcvLviXcruQxfJGlpy0v8ZB-P4fNoU5Zrl7QdBuVtGJNsEWTl1f-DqOWCct4UcLoDdQwpRdsf_oKg3NqTW3vyYK8EXt5v8Aff67oHbIO_x4JLxCRnv0q8-icg-3EYsv2WC_liR96mYvKAEsgaXCT8BA3puCQ</recordid><startdate>20010717</startdate><enddate>20010717</enddate><creator>Hadari, Y R</creator><creator>Gotoh, N</creator><creator>Kouhara, H</creator><creator>Lax, I</creator><creator>Schlessinger, J</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20010717</creationdate><title>Critical Role for the Docking-Protein FRS2α in FGF Receptor-Mediated Signal Transduction Pathways</title><author>Hadari, Y R ; Gotoh, N ; Kouhara, H ; Lax, I ; Schlessinger, J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-e5333c1139ab3a35b06d2cc8107d848b86e10af5b830d819597dd33b2256183f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Adaptor Proteins, Signal Transducing</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Binding sites</topic><topic>Biological Sciences</topic><topic>Cell Division</topic><topic>Cell growth</topic><topic>Cell Line</topic><topic>Cell lines</topic><topic>Cell Movement</topic><topic>Complementary DNA</topic><topic>Delta cells</topic><topic>Embryos</topic><topic>Fibroblast Growth Factor 1</topic><topic>Fibroblast Growth Factor 2 - metabolism</topic><topic>Fibroblasts</topic><topic>FRS2^a protein</topic><topic>Gab1 protein</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Membrane Proteins - physiology</topic><topic>Mice</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoproteins - genetics</topic><topic>Phosphoproteins - metabolism</topic><topic>Phosphoproteins - physiology</topic><topic>Phosphorylation</topic><topic>Polymerase chain reaction</topic><topic>Receptors, Fibroblast Growth Factor - metabolism</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hadari, Y R</creatorcontrib><creatorcontrib>Gotoh, N</creatorcontrib><creatorcontrib>Kouhara, H</creatorcontrib><creatorcontrib>Lax, I</creatorcontrib><creatorcontrib>Schlessinger, J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hadari, Y R</au><au>Gotoh, N</au><au>Kouhara, H</au><au>Lax, I</au><au>Schlessinger, J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Critical Role for the Docking-Protein FRS2α in FGF Receptor-Mediated Signal Transduction Pathways</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2001-07-17</date><risdate>2001</risdate><volume>98</volume><issue>15</issue><spage>8578</spage><epage>8583</epage><pages>8578-8583</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The docking protein FRS2α has been implicated as a mediator of signaling via fibroblast growth factor receptors (FGFRs). 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| subjects | Adaptor Proteins, Signal Transducing Animals Antibodies Binding sites Biological Sciences Cell Division Cell growth Cell Line Cell lines Cell Movement Complementary DNA Delta cells Embryos Fibroblast Growth Factor 1 Fibroblast Growth Factor 2 - metabolism Fibroblasts FRS2^a protein Gab1 protein Membrane Proteins - genetics Membrane Proteins - metabolism Membrane Proteins - physiology Mice Mitogen-Activated Protein Kinases - metabolism Phosphatidylinositol 3-Kinases - metabolism Phosphoproteins - genetics Phosphoproteins - metabolism Phosphoproteins - physiology Phosphorylation Polymerase chain reaction Receptors, Fibroblast Growth Factor - metabolism Signal Transduction |
| title | Critical Role for the Docking-Protein FRS2α in FGF Receptor-Mediated Signal Transduction Pathways |
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