Sef Inhibits Fibroblast Growth Factor Signaling by Inhibiting FGFR1 Tyrosine Phosphorylation and Subsequent ERK Activation
Signaling through fibroblast growth factor receptors (FGFRs) is essential for many cellular processes including proliferation and migration as well as differentiation events such as angiogenesis, osteogenesis, and chondrogenesis. Recently, genetic screens in Drosophila and gene expression screens in...
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| Veröffentlicht in: | The Journal of biological chemistry 2003-04, Vol.278 (16), p.14087-14091 |
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| creator | Kovalenko, Dmitry Yang, Xuehui Nadeau, Robert J. Harkins, Lauren K. Friesel, Robert |
| description | Signaling through fibroblast growth factor receptors (FGFRs) is essential for many cellular processes including proliferation and migration as well as differentiation events such as angiogenesis, osteogenesis, and chondrogenesis. Recently, genetic screens in Drosophila and gene expression screens in zebrafish have resulted in the identification of several feedback inhibitors of FGF signaling. One of these, Sef (similarexpression to fgf genes), encodes a transmembrane protein that belongs to the FGF synexpression group. Here we show that like zebrafish Sef (zSef), mouse Sef (mSef) interacts with FGFR1 and that the cytoplasmic domain of mSef mediates this interaction. Overexpression of mSef in NIH3T3 cells results in a decrease in FGF-induced cell proliferation associated with a decrease in Tyr phosphorylation of FGFR1 and FRS2. As a consequence, there is a reduction in the phosphorylation of Raf-1 at Ser338, MEK1/2 at Ser217 and Ser221, and ERK1/2 at Thr202 and Tyr204. Furthermore, mSef inhibits ERK activation mediated by a constitutively activated FGFR1 but not by a constitutively active Ras and decreases FGF but not PDGF-mediated activation of Akt. These results indicate that Sef exerts its inhibitory effects at the level of FGFR and upstream of Ras providing an additional level of negative regulation of FGF signaling. |
| doi_str_mv | 10.1074/jbc.C200606200 |
| format | Article |
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Recently, genetic screens in Drosophila and gene expression screens in zebrafish have resulted in the identification of several feedback inhibitors of FGF signaling. One of these, Sef (similarexpression to fgf genes), encodes a transmembrane protein that belongs to the FGF synexpression group. Here we show that like zebrafish Sef (zSef), mouse Sef (mSef) interacts with FGFR1 and that the cytoplasmic domain of mSef mediates this interaction. Overexpression of mSef in NIH3T3 cells results in a decrease in FGF-induced cell proliferation associated with a decrease in Tyr phosphorylation of FGFR1 and FRS2. As a consequence, there is a reduction in the phosphorylation of Raf-1 at Ser338, MEK1/2 at Ser217 and Ser221, and ERK1/2 at Thr202 and Tyr204. Furthermore, mSef inhibits ERK activation mediated by a constitutively activated FGFR1 but not by a constitutively active Ras and decreases FGF but not PDGF-mediated activation of Akt. 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These results indicate that Sef exerts its inhibitory effects at the level of FGFR and upstream of Ras providing an additional level of negative regulation of FGF signaling.</description><subject>3T3 Cells</subject><subject>Adenoviridae - genetics</subject><subject>Animals</subject><subject>Cell Division</subject><subject>Cell Line</subject><subject>Cloning, Molecular</subject><subject>COS Cells</subject><subject>Danio rerio</subject><subject>Enzyme Activation</subject><subject>Fibroblast Growth Factors - metabolism</subject><subject>Freshwater</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Genetic Vectors</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>MAP Kinase Kinase 1</subject><subject>MAP Kinase Kinase 2</subject><subject>Membrane Proteins - metabolism</subject><subject>Membrane Proteins - physiology</subject><subject>Mice</subject><subject>Mitogen-Activated Protein Kinase Kinases - metabolism</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Platelet-Derived Growth Factor - metabolism</subject><subject>Precipitin Tests</subject><subject>Protein Structure, Tertiary</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Receptor Protein-Tyrosine Kinases - metabolism</subject><subject>Receptor, Fibroblast Growth Factor, Type 1</subject><subject>Receptors, Fibroblast Growth Factor - metabolism</subject><subject>Serine - metabolism</subject><subject>Signal Transduction</subject><subject>Threonine - metabolism</subject><subject>Thymidine - metabolism</subject><subject>Tyrosine - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFrGzEQhUVpaNyk1x6LDiW3dSXtrlZ7DCbrhgYa4hR6E5J21quwllxJTnB_fZXaJacSHUYM880w8x5CHymZU9JUXx60mS8YIZzwHN-gGSWiLMqa_nyLZoQwWrSsFqfofYwPJL-qpe_QKWWcVJzyGfq9ggFfu9FqmyLurA5eTyomvAz-KY24Uyb5gFd27dRk3Rrr_T_8OeuW3R3F9_vgo3WAb0cft6MP-0kl6x1WrsernY7wawcu4au7b_jSJPv4t3qOTgY1Rfhw_M_Qj-7qfvG1uPm-vF5c3hSmJjwVoMtel0JxpXWvWWUYB4Ba6ZK1BPigmChrMfQt1DpHYkRTU1qDaImoDBflGbo4zN0Gn_eISW5sNDBNyoHfRdmUjGSR-KsgFVm-StAMzg-gyXfHAIPcBrtRYS8pkc-2yGyLfLElN3w6Tt7pDfQv-NGHDHw-AKNdj082gNTWmxE2kjVCUi5pRUSTMXHAIOv1aCHIaCw4A31uMUn23v5vhT9JFqhj</recordid><startdate>20030418</startdate><enddate>20030418</enddate><creator>Kovalenko, Dmitry</creator><creator>Yang, Xuehui</creator><creator>Nadeau, Robert J.</creator><creator>Harkins, Lauren K.</creator><creator>Friesel, Robert</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><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>F1W</scope><scope>H95</scope><scope>L.G</scope><scope>7X8</scope></search><sort><creationdate>20030418</creationdate><title>Sef Inhibits Fibroblast Growth Factor Signaling by Inhibiting FGFR1 Tyrosine Phosphorylation and Subsequent ERK Activation</title><author>Kovalenko, Dmitry ; Yang, Xuehui ; Nadeau, Robert J. ; Harkins, Lauren K. ; Friesel, Robert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c506t-eb3db38a6abbdb24c26eee5ab3290e6fa28358fd9e5bfd90c875115e89084c683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>3T3 Cells</topic><topic>Adenoviridae - genetics</topic><topic>Animals</topic><topic>Cell Division</topic><topic>Cell Line</topic><topic>Cloning, Molecular</topic><topic>COS Cells</topic><topic>Danio rerio</topic><topic>Enzyme Activation</topic><topic>Fibroblast Growth Factors - metabolism</topic><topic>Freshwater</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Genetic Vectors</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>MAP Kinase Kinase 1</topic><topic>MAP Kinase Kinase 2</topic><topic>Membrane Proteins - metabolism</topic><topic>Membrane Proteins - physiology</topic><topic>Mice</topic><topic>Mitogen-Activated Protein Kinase Kinases - metabolism</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Platelet-Derived Growth Factor - metabolism</topic><topic>Precipitin Tests</topic><topic>Protein Structure, Tertiary</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Receptor Protein-Tyrosine Kinases - metabolism</topic><topic>Receptor, Fibroblast Growth Factor, Type 1</topic><topic>Receptors, Fibroblast Growth Factor - metabolism</topic><topic>Serine - metabolism</topic><topic>Signal Transduction</topic><topic>Threonine - metabolism</topic><topic>Thymidine - metabolism</topic><topic>Tyrosine - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kovalenko, Dmitry</creatorcontrib><creatorcontrib>Yang, Xuehui</creatorcontrib><creatorcontrib>Nadeau, Robert J.</creatorcontrib><creatorcontrib>Harkins, Lauren K.</creatorcontrib><creatorcontrib>Friesel, Robert</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 1: Biological Sciences & Living Resources</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) Professional</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kovalenko, Dmitry</au><au>Yang, Xuehui</au><au>Nadeau, Robert J.</au><au>Harkins, Lauren K.</au><au>Friesel, Robert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sef Inhibits Fibroblast Growth Factor Signaling by Inhibiting FGFR1 Tyrosine Phosphorylation and Subsequent ERK Activation</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2003-04-18</date><risdate>2003</risdate><volume>278</volume><issue>16</issue><spage>14087</spage><epage>14091</epage><pages>14087-14091</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Signaling through fibroblast growth factor receptors (FGFRs) is essential for many cellular processes including proliferation and migration as well as differentiation events such as angiogenesis, osteogenesis, and chondrogenesis. Recently, genetic screens in Drosophila and gene expression screens in zebrafish have resulted in the identification of several feedback inhibitors of FGF signaling. One of these, Sef (similarexpression to fgf genes), encodes a transmembrane protein that belongs to the FGF synexpression group. Here we show that like zebrafish Sef (zSef), mouse Sef (mSef) interacts with FGFR1 and that the cytoplasmic domain of mSef mediates this interaction. Overexpression of mSef in NIH3T3 cells results in a decrease in FGF-induced cell proliferation associated with a decrease in Tyr phosphorylation of FGFR1 and FRS2. As a consequence, there is a reduction in the phosphorylation of Raf-1 at Ser338, MEK1/2 at Ser217 and Ser221, and ERK1/2 at Thr202 and Tyr204. Furthermore, mSef inhibits ERK activation mediated by a constitutively activated FGFR1 but not by a constitutively active Ras and decreases FGF but not PDGF-mediated activation of Akt. These results indicate that Sef exerts its inhibitory effects at the level of FGFR and upstream of Ras providing an additional level of negative regulation of FGF signaling.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>12604616</pmid><doi>10.1074/jbc.C200606200</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2003-04, Vol.278 (16), p.14087-14091 |
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| subjects | 3T3 Cells Adenoviridae - genetics Animals Cell Division Cell Line Cloning, Molecular COS Cells Danio rerio Enzyme Activation Fibroblast Growth Factors - metabolism Freshwater Gene Expression Regulation, Enzymologic Genetic Vectors Humans Immunoblotting MAP Kinase Kinase 1 MAP Kinase Kinase 2 Membrane Proteins - metabolism Membrane Proteins - physiology Mice Mitogen-Activated Protein Kinase Kinases - metabolism Mitogen-Activated Protein Kinases - metabolism Phosphorylation Platelet-Derived Growth Factor - metabolism Precipitin Tests Protein Structure, Tertiary Protein-Serine-Threonine Kinases - metabolism Protein-Tyrosine Kinases - metabolism Receptor Protein-Tyrosine Kinases - metabolism Receptor, Fibroblast Growth Factor, Type 1 Receptors, Fibroblast Growth Factor - metabolism Serine - metabolism Signal Transduction Threonine - metabolism Thymidine - metabolism Tyrosine - metabolism |
| title | Sef Inhibits Fibroblast Growth Factor Signaling by Inhibiting FGFR1 Tyrosine Phosphorylation and Subsequent ERK Activation |
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