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Mol. Cell. Biol. 22 (3): 916-926

Copyright © 2002 by the American Society for Microbiology. All rights reserved.

The RAS Effector RIN1 Directly Competes with RAF and Is Regulated by 14-3-3 Proteins

Ying Wang,1,2 Richard T. Waldron,2,3,4 Ajay Dhaka,1,2 Apoor Patel,1,2 Maggie M. Riley,1,2 Enrique Rozengurt,2,3,4 and John Colicelli1,2*

Department of Biological Chemistry,1 Department of Medicine,3 CURE Digestive Diseases Research Center,4 Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California 900952

Received for publication 29 August 2001. Revision received 16 October 2001. Accepted for publication 2 November 2001.

Abstract: Activation of RAS proteins can lead to multiple outcomes by virtue of regulated signal traffic through alternate effector pathways. We demonstrate that the RAS effector protein RIN1 binds to activated RAS with an affinity (Kd, 22 nM) similar to that observed for RAF1. At concentrations close to their equilibrium dissociation constant values, RIN1 and RAF1 compete directly for RAS binding. RIN1 was also observed to inhibit cellular transformation by activated mutant RAS. This distinguishes RIN1 from other RAS effectors, which are transformation enhancing. Blockade of transformation was mediated by the RAS binding domain but required membrane localization. RIN1 recognizes endogenous RAS following transient activation by epidermal growth factor, and a portion of RIN1 fractionates to the cell membrane in a manner consistent with a reversible interaction. RIN1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of RIN1 and led to more efficient blockade of RAS-mediated transformation. The mutant protein, RIN1S351A, showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase D (PKD [also known as PKCµ]) in vitro and in vivo. These data suggest that the normal localization and function of RIN1, as well as its ability to compete with RAF, are regulated in part by 14-3-3 binding, which in turn is controlled by PKD phosphorylation.

* Corresponding author. Mailing address: Department of Biological Chemistry, UCLA, Los Angeles, CA 90095. Phone: (310) 625-5272. Fax: (310) 206-5272. E-mail: colicelli{at}mednet.ucla.edu.

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