Co-Authors:
Ziv, I., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Fuchs, Y., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Preger, E., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Shabtay, A., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel, Dept. of Cattle and Genetic Sciences, Institute of Animal Science, Agricultural Research Organization Newe-Ya'ar Research Center, Ramat Yishay 30095, Israel
Harduf, H., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel, 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
Zilpa, T., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Dym, N., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Ron, D., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Abstract:
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 downregulation 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. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
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