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J. Biol. Chem., Vol. 281, Issue 51, 39225-39235, December 22, 2006

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The Human Sef-a Isoform Utilizes Different Mechanisms to Regulate Receptor Tyrosine Kinase Signaling Pathways and Subsequent Cell Fate^*

From the Department of Biology, Technion Institute of Technology, Haifa 32000, Israel

Negative feedback is among the key mechanisms for regulating receptor tyrosine kinase (RTK) signaling. Human Sef, a recently identified inhibitor of RTK signaling, encodes different isoforms, including a membrane spanning (hSef-a) and a cytosolic (hSef-b) isoform. Previously, we reported that hSef-b inhibited fibroblast proliferation and prevented the activation of mitogen-activated protein kinase (MAPK), without affecting protein kinase B/Akt or p38 MAPK. Conflicting results were reported concerning hSef-a inhibition of MAPK activation, and the effect of hSef-a on other RTK-induced signaling pathways is unknown. Here we show that, in fibroblasts, similar to hSef-b, ectopic expression of hSef-a inhibited fibroblast growth factor-induced cell proliferation. Unlike hSef-b, however, the growth arrest was mediated via a MAPK-independent mechanism, and was accompanied by elevated p38 MAPK phosphorylation and inhibition of protein kinase B/Akt. In addition, hSef-a, but not hSef-b, mediated apoptosis in fibroblast growth factor-stimulated cells. Chemical inhibitor of p38 MAPK abrogated the effect of hSef-a on apoptosis. In epithelial cells, ectopic expression of hSef-a inhibited the activation of MAPK, whereas down-regulation of endogenous hSef-a significantly increased MAPK activation and accelerated growth factor-dependent cell proliferation. These results indicate that hSef-a is a multifunctional negative modulator of RTK signaling and clearly demonstrate that hSef-a can inhibit the activation of MAPK, although in a cell type-specific manner. Moreover, the differences between the activities of hSef-a and hSef-b suggest that hSef isoforms can control signal specificity and subsequent cell fate by utilizing different mechanisms to modulate RTK signaling.

Received for publication, August 2, 2006 , and in revised form, September 28, 2006.

^* This work was supported by a grant from the German-Israeli Niedersachsen joined fund (Grant D-30163 to D. R.). 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.

¹ Both authors contributed equally to this work.

² Present address: Dept. of Cattle and Genetic Sciences, Institute of Animal Science, Agricultural Research Organization Newe-Ya'ar Research Center, Ramat Yishay 30095, Israel.

³ Present address: Laboratory for Research in Reproductive Sciences, Dept. of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula, Israel Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

⁴ To whom correspondence should be addressed: Tel.: 972-4-829-4217; Fax: 972-4-822-5153; E-mail: dinar{at}techunix.technion.ac.il.

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