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Molecular and Cellular Biology, March 2008, p. 1573-1583, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01087-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Integration of Transforming Growth Factor β and RAS Signaling Silences a RAB5 Guanine Nucleotide Exchange Factor and Enhances Growth Factor-Directed Cell Migration{triangledown}

Hailiang Hu, Marc Milstein, Joanne M. Bliss, Minh Thai, Gautam Malhotra, Lucia C. Huynh, and John Colicelli*

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

Received 19 June 2007/ Returned for modification 1 August 2007/ Accepted 10 December 2007

Transforming growth factor β (TGF-β) receptor (TβR) 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 TβR signaling through enhanced endocytosis. TβR activation induces SNAI1 (Snail), a transcription repressor that reduces RIN1 expression, providing a negative feedback mechanism to control TβR 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-β-induced RIN1 silencing in breast cancer cells prolonged sensitivity to hepatocyte growth factor, a ligand for the MET-type RTK, and enhanced growth factor-directed cell motility. We conclude that in some tumor cells TβR 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-β signaling by normal versus transformed cells.

* Corresponding author. Mailing address: Department of Biological Chemistry, Jonsson Comprehensive Cancer Center and Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095. Phone: (310) 625-5272. Fax: (310) 206-5272. E-mail: colicelli{at}mednet.ucla.edu

{triangledown} Published ahead of print on 26 December 2007.

Molecular and Cellular Biology, March 2008, p. 1573-1583, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01087-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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