ZFIN ID: ZDB-PUB-040127-2
Alternative splicing generates an isoform of the human Sef gene with altered subcellular localization and specificity
Preger, E., Ziv, I., Shabtay, A., Sher, I., Tsang, M., Dawid, I.B., Altuvia, Y., and Ron, D.
Date: 2004
Source: Proceedings of the National Academy of Sciences of the United States of America   101(5): 1229-1234 (Journal)
Registered Authors: Dawid, Igor B., Tsang, Michael
Keywords: none
MeSH Terms:
  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Cell Division
  • Cloning, Molecular
  • Cyclin D1/analysis
  • MAP Kinase Signaling System
  • Mice
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Organ Specificity
  • Protein Isoforms
  • Receptors, Interleukin/genetics*
PubMed: 14742870 Full text @ Proc. Natl. Acad. Sci. USA
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.