title: Sef inhibits fibroblast growth factor signaling by inhibiting FGFR1 tyrosine phosphorylation and subsequent ERK activation.
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 (similar expression 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 Ser(338), MEK1/2 at Ser(217) and Ser(221), and ERK1/2 at Thr(202) and Tyr(204). 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.
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough 04074-7205, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Kovalenko
authors.forename: Xuehui
authors.initials: X
authors.lastname: Yang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nadeau
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Harkins
authors.forename: Robert
authors.initials: R
authors.lastname: Friesel
mesh_terms: D016475:3T3 Cells; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002455:Cell Division; D002460:Cell Line; D003001:Cloning, Molecular; D004789:Enzyme Activation; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor; D017468:Receptors, Fibroblast Growth Factor; C469338:Sef protein, mouse; D013912:Threonine; D014443:Tyrosine; D012694:Serine; D005346:Fibroblast Growth Factors; C482128:MAP2K2 protein, human; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D013936:Thymidine