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J. Biol. Chem., Vol. 278, Issue 50, 50273-50282, December 12, 2003

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hSef Inhibits PC-12 Cell Differentiation by Interfering with Ras-Mitogen-activated Protein Kinase MAPK Signaling^*

Shiqin Xiong, Qiuhui Zhao, Zhili Rong, Guanrong Huang, Yiling Huang, Peila Chen, Shuping Zhang, Li Liu, and Zhijie Chang

From the Tsinghua Institute of Genome Research, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084,China

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.

Received for publication, June 30, 2003 , and in revised form, August 25, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF494208 (hSef), AF494210 (mSef), AF494211 (hSef-S), and AF494209 (mSef-S).

^* This work was supported in part by research Grants 39970369, 30070703, and 30030050 from the Chinese National Academic Foundation, Grants 2001CB510006 and 2002CB51300 from the 973 National Key Basic Research Program of China, and Beijing Scientific Research Grant H020220020310, and the 985 foundation of Tsinghua University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 86-10-62785076; Fax: 86-10-62773624; E-mail: zhijiec{at}mail.tsinghua.edu.cn.

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