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Mol. Cell. Biol. doi:10.1128/MCB.01087-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Integration of TGF and RAS Signaling Silences a RAB5 GEF and Enhances Growth Factor-Directed Cell Migration

Department of Biological Chemistry, Jonsson Comprehensive Cancer Center and Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095

^* To whom correspondence should be addressed. Email: colicelli{at}mednet.ucla.edu.

	Abstract

Transforming growth factor receptor (TR) signaling contributes to normal development as well as tumorigenesis. Here we report that RIN1, a RAB5 guanine nucleotide exchange factor (GEF) and down regulator of receptor tyrosine kinases (RTKs), promotes TR signaling through enhanced endocytosis. TR activation induces SNAI1 (Snail), a transcription repressor that reduces RIN1 expression, providing a negative feedback mechanism to control TR trafficking and downstream signaling. Persistent RAS signaling disrupts this equilibrium by stabilizing SNAI1 protein resulting in strong silencing of RIN1 and stabilization of RTKs. TGF-induced RIN1 silencing in breast cancer cells prolonged sensitivity to hepatocyte growth factor (HGF), a ligand for the MET type RTK, and enhanced growth factor-directed cell motility. We conclude that in some tumor cells TR and RAS signals are integrated through the silencing of RIN1, leading to a reduction in RAB5-mediated endocytosis. These findings shed new light on the basis for distinct interpretations of TGF signaling by normal versus transformed cells.