Preger, E., Department of Biology, Technion-Israel Inst. of Technology, Haifa 32000, Israel
Ziv, I., Department of Biology, Technion-Israel Inst. of Technology, Haifa 32000, Israel
Shabtay, A., Department of Biology, Technion-Israel Inst. of Technology, Haifa 32000, Israel
Sher, I., Department of Biology, Technion-Israel Inst. of Technology, Haifa 32000, Israel
Tsang, M., Laboratory of Molecular Genetics, Natl. Inst. of Child Hlth./Hum. Dev., National Institutes of Health, Bethesda, MD 20892, United States
Dawid, I.B., Laboratory of Molecular Genetics, Natl. Inst. of Child Hlth./Hum. Dev., National Institutes of Health, Bethesda, MD 20892, United States
Altuvia, Y., Dept. of Molec. Genet. and Biotech., Hebrew University-Hadassah Med. Sch., Jerusalem 91120, Israel
Ron, D., Department of Biology, Technion-Israel Inst. of Technology, Haifa 32000, Israel
Ziv, I., Department of Biology, Technion-Israel Inst. of Technology, Haifa 32000, Israel
Shabtay, A., Department of Biology, Technion-Israel Inst. of Technology, Haifa 32000, Israel
Sher, I., Department of Biology, Technion-Israel Inst. of Technology, Haifa 32000, Israel
Tsang, M., Laboratory of Molecular Genetics, Natl. Inst. of Child Hlth./Hum. Dev., National Institutes of Health, Bethesda, MD 20892, United States
Dawid, I.B., Laboratory of Molecular Genetics, Natl. Inst. of Child Hlth./Hum. Dev., National Institutes of Health, Bethesda, MD 20892, United States
Altuvia, Y., Dept. of Molec. Genet. and Biotech., Hebrew University-Hadassah Med. Sch., Jerusalem 91120, Israel
Ron, D., Department of Biology, Technion-Israel Inst. of Technology, Haifa 32000, Israel
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.
