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Vol. 17, Issue 7, 3108-3121, July 2006

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Multiple Sequence Elements Facilitate Chp Rho GTPase Subcellular Location, Membrane Association, and Transforming Activity

Emily J. Chenette^*,, Natalia Y. Mitin^,, and Channing J. Der^*,,

*Curriculum in Genetics and Molecular Biology, Department of Pharmacology, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295

Submitted September 27, 2005; Revised April 18, 2006; Accepted April 19, 2006
J. Silvio Gutkind

Cdc42 homologous protein (Chp) is a member of the Rho family of small GTPases and shares significant sequence and functional similarity with Cdc42. However, unlike classical Rho GTPases, we recently found that Chp depends on palmitoylation, rather than prenylation, for association with cellular membranes. Because palmitoylation alone is typically not sufficient to promote membrane association, we evaluated the possibility that other carboxy-terminal residues facilitate Chp subcellular association with membranes. We found that Chp membrane association and transforming activity was dependent on the integrity of a stretch of basic amino acids in the carboxy terminus of Chp and that the basic amino acids were not simply part of a palmitoyl acyltransferase recognition motif. We also determined that the 11 carboxy-terminal residues alone were sufficient to promote Chp plasma and endomembrane association. Interestingly, stimulation with tumor necrosis factor- activated only endomembrane-associated Chp. Finally, we found that Chp membrane association was not disrupted by Rho guanine nucleotide dissociation inhibitory proteins, which are negative regulators of Cdc42 membrane association and biological activity. In summary, the unique carboxy-terminal sequence elements that promote Chp subcellular location and function expand the complexity of mechanisms by which the cellular functions of Rho GTPases are regulated.

Address correspondence to: Channing J. Der ( cjder{at}med.unc.edu)

Abbreviations used: biotin-BMCC, 1-biotinamido-4-[4'-(maleimidomethyl) cyclohexanecarboxamido] butane; CAAX, cysteine (C) aliphatic amino acid (A) aliphatic amino acid (A) terminal amino acid (X); Chp, Cdc42 homologous protein; HA, hemagglutinin; RhoGDI, Rho guanine nucleotide disassociation inhibitor; GST, glutathione S-transferase; GFP, green fluorescent protein; PAK, p21 activated kinase; PBD, p21 binding domain; TNF, tumor necrosis factor; YFP, yellow fluorescent protein

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