Sef-S, an alternative splice isoform of sef gene, inhibits NIH3T3 cell proliferation via a mitogen-activated protein kinases p42 and p44 (ERK1/2)-independent mechanism

Cell Signal. 2007 Jan;19(1):93-102. doi: 10.1016/j.cellsig.2006.05.033. Epub 2006 Jun 8.

Abstract

sef (similar expression to fgf genes) was recently identified as a negative regulator of fibroblast growth factor (FGF) signaling in zebrafish, chicken, mouse and human. By repressing events upstream and/or downstream Ras, Sef inhibits FGF-induced ERK activation and cell proliferation. Here we report that Sef-S, an alternative splice isoform of Sef, lacks a signal peptide and is localized in cytosol. Sef-S inhibits FGF-induced NIH3T3 cell proliferation, a similar function to Sef. However, Sef-S represses neither the intensity nor the duration of ERK activation. Moreover, Sef-S does not inhibit Elk1-dependent transcription. Our study revealed that the signal peptide is critical for the different activities between Sef and Sef-S in FGF-Ras-MAPK signaling cascades. Furthermore, we observed that Sef-S associated with FGFR2 in a co-immunoprecipitated complex. These results indicate that Sef-S inhibits FGF-induced NIH3T3 cell proliferation via an ERK-independent mechanism and therefore suggest that alternative splice licenses sef gene to inhibit cell proliferation via multiple signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Proliferation*
  • Cytosol / metabolism
  • Enzyme Activation
  • Fibroblast Growth Factors / physiology
  • Membrane Proteins / physiology*
  • Mice
  • Mitogen-Activated Protein Kinase 1 / physiology*
  • Mitogen-Activated Protein Kinase 3 / physiology*
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Protein Isoforms / physiology
  • Protein Sorting Signals
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Signal Transduction
  • Transcriptional Activation
  • ets-Domain Protein Elk-1 / metabolism

Substances

  • Elk1 protein, mouse
  • Membrane Proteins
  • Protein Isoforms
  • Protein Sorting Signals
  • Sef protein, mouse
  • ets-Domain Protein Elk-1
  • Fibroblast Growth Factors
  • Fgfr2 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 2
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3