title: Alternative splicing generates an isoform of the human Sef gene with altered subcellular localization and specificity.
abstract: Receptor tyrosine kinases (RTKs) control a multitude of biological processes and are therefore subjected to multiple levels of regulation. Negative feedback is one of the mechanisms that provide an effective means to control RTK-mediated signaling. Sef has recently been identified as a specific antagonist of fibroblast growth factor (FGF) signaling in zebrafish and subsequently in mouse and human. Sef encodes a putative type I transmembrane protein that antagonizes the Ras/mitogen-activated protein kinase pathway in all three species. Mouse Sef was also shown to inhibit the phosphatidylinositol 3-kinase pathway. We show here that an alternative splicing mechanism generates an isoform of human Sef, hSef-b, which unlike the previously reported Sef (hSef-a) is a cytosolic protein. Contrary to hSef-a, which is ubiquitously expressed, hSef-b transcripts display a restricted pattern of expression in human tissues. hSef-b inhibits FGF-induced cell proliferation and prevents the activation of mitogen-activated protein kinase without affecting the upstream component MAPK kinase. Furthermore, hSef-b does not antagonize FGF induction of the phosphatidylinositol 3-kinase pathway. In addition to the effects on FGF signaling, hSef-b inhibited cellular response to platelet-derived growth factor but not other RTK ligands. Therefore, alternative splicing of the hSef gene expands the Sef feedback inhibition repertoire of RTK signaling.
authors.affiliation: Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Preger
authors.forename: Inbal
authors.initials: I
authors.lastname: Ziv
authors.forename: Ariel
authors.initials: A
authors.lastname: Shabtay
authors.forename: Ifat
authors.initials: I
authors.lastname: Sher
authors.forename: Michael
authors.initials: M
authors.lastname: Tsang
authors.forename: Igor B
authors.initials: IB
authors.lastname: Dawid
authors.forename: Yael
authors.initials: Y
authors.lastname: Altuvia
authors.forename: Dina
authors.initials: D
authors.lastname: Ron
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division; D003001:Cloning, Molecular; D019938:Cyclin D1 / Q000032:analysis; D020935:MAP Kinase Signaling System; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009928:Organ Specificity; D020033:Protein Isoforms; D018123:Receptors, Interleukin / Q000235:genetics*
chemical_list: C477526:IL17RD protein, human; D020033:Protein Isoforms; D018123:Receptors, Interleukin; D019938:Cyclin D1