Abstract
Growth factor signaling by receptor tyrosine kinases regulates several cell fates, such as proliferation and differentiation. Sef was genetically identified as a negative regulator of fibroblast growth factor (FGF) signaling. Using bioinformatic methods and rapid amplification of cDNA ends-PCR, we isolated both the mouse and the human Sef genes, which encoded the Sef protein and Sef-S isoform that was generated through alternative splicing. We provide evidence that the Sef gene products were located mainly on the cell membrane. Co-immunoprecipitation and immunostaining experiments indicate that hSef interacts with FGFR1 and FGFR2 but not FGFR3. Our results demonstrated that stably expressed hSef strongly inhibits FGF2- or nerve growth factor-induced PC-12 cell differentiation. The intracellular domain of hSef is necessary for the inhibitory effect on FGF2-induced PC-12 cell differentiation. Furthermore, our data suggested Sef exerted the negative effect on FGF2-induced PC-12 cell differentiation through the prevention of Ras-mitogen-activated protein kinase signaling, possibly functioning upstream of the Ras molecule. These findings suggest that Sef may play an important role in the regulation of PC-12 cell differentiation.
Highlights
Cell growth and differentiation mediated by receptor tyrosine kinases are regulated by many extracellular signals, most of which activate the Ras-MAPK1 kinase cascade [1,2,3,4]
Our results demonstrated that stably expressed hSef strongly inhibits FGF2- or nerve growth factorinduced PC-12 cell differentiation
Using PC-12 cell lines as a model, we demonstrate that overexpression of hSef significantly inhibited FGF2- or NGF-induced PC-12 cell differentiation. hSef, as a negative regulator of fibroblast growth factor (FGF) signaling pathway, exerted an inhibitory effect on PC-12 cell differentiation, possibly through prevention of FGFR-RasMAPK signaling on molecules upstream of Ras
Summary
Cell growth and differentiation mediated by receptor tyrosine kinases are regulated by many extracellular signals, most of which activate the Ras-MAPK1 kinase cascade [1,2,3,4]. Our results demonstrated that stably expressed hSef strongly inhibits FGF2- or nerve growth factorinduced PC-12 cell differentiation. The intracellular domain of hSef is necessary for the inhibitory effect on FGF2-induced PC-12 cell differentiation.
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