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Molecular and Cellular Biology, June 2002, p. 4053-4061, Vol. 22, No. 12
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.12.4053-4061.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Leukemia-Associated Rho Guanine Nucleotide Exchange Factor Promotes G{alpha}q-Coupled Activation of RhoA

Michelle A. Booden,1* David P. Siderovski,1,2 and Channing J. Der1

Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill,1 University of North Carolina Neuroscience Center, Chapel Hill, North Carolina 275992

Received 16 January 2002/ Returned for modification 4 March 2002/ Accepted 15 March 2002

Leukemia-associated Rho guanine-nucleotide exchange factor (LARG) belongs to the subfamily of Dbl homology RhoGEF proteins (including p115 RhoGEF and PDZ-RhoGEF) that possess amino-terminal regulator of G protein signaling (RGS) boxes also found within GTPase-accelerating proteins (GAPs) for heterotrimeric G protein {alpha} subunits. p115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G{alpha}12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation. The presence of RGS box and Dbl homology domains within LARG suggests this protein may also function as a GAP toward specific G{alpha} subunits and couple G{alpha} activation to RhoA-mediating signaling pathways. Unlike the RGS box of p115 RhoGEF, the RGS box of LARG interacts not only with G{alpha}12 and G{alpha}13 but also with G{alpha}q. In cellular coimmunoprecipitation studies, the LARG RGS box formed stable complexes with the transition state mimetic forms of G{alpha}q, G{alpha}12, and G{alpha}13. Expression of the LARG RGS box diminished the transforming activity of oncogenic G protein-coupled receptors (Mas, G2A, and m1-muscarinic cholinergic) coupled to G{alpha}q and G{alpha}13. Activated G{alpha}q, as well as G{alpha}12 and G{alpha}13, cooperated with LARG and caused synergistic activation of RhoA, suggesting that all three G{alpha} subunits stimulate LARG-mediated activation of RhoA. Our findings suggest that the RhoA exchange factor LARG, unlike the related p115 RhoGEF and PDZ-RhoGEF proteins, can serve as an effector for Gq-coupled receptors, mediating their functional linkage to RhoA-dependent signaling pathways.

* Corresponding author. Mailing address: University of North Carolina at Chapel Hill, CB 7295, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599. Phone: (919) 962-1057. Fax: (919) 966-0162. E-mail: mbooden{at}med.unc.edu.

Molecular and Cellular Biology, June 2002, p. 4053-4061, Vol. 22, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.12.4053-4061.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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