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.
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.
Rong
Zhili
Z
Tsinghua Institute of Genome Research, Department of Biological Sciences and Biotechnology, and School of Medicine, Tsinghua University, Beijing 100084, China.
Ren
Yongming
Y
Cheng
Long
L
Li
Zhiyong
Z
Li
Yinghua
Y
Sun
Yang
Y
Li
Hongge
H
Xiong
Shiqin
S
Chang
Zhijie
Z
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D005346:Fibroblast Growth Factors / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D020033:Protein Isoforms / Q000502:physiology; D021382:Protein Sorting Signals; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
C494113:Elk1 protein, mouse; D008565:Membrane Proteins; D020033:Protein Isoforms; D021382:Protein Sorting Signals; C469338:Sef protein, mouse; D050807:ets-Domain Protein Elk-1; D005346:Fibroblast Growth Factors; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3