Alternative splicing generates an isoform of the human Sef gene with altered subcellular localization and specificity

Ella Preger, Inbal Ziv, Ariel Shabtay, Ifat Sher, Michael Tsang, Igor B. Dawid, Yael Altuvia, Dina Ron*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


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.

Original languageAmerican English
Pages (from-to)1229-1234
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
StatePublished - 3 Feb 2004


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