TY - JOUR
T1 - Leukemia-associated Rho guanine nucleotide exchange factor promotes Gαq-coupled activation of RhoA
AU - Booden, Michelle A.
AU - Siderovski, David P.
AU - Der, Channing J.
PY - 2002
Y1 - 2002
N2 - 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 α subunits. p115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of Gα12/13 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 Gα subunits and couple Gα activation to RhoA-mediating signaling pathways. Unlike the RGS box of p115 RhoGEF, the RGS box of LARG interacts not only with Gα12 and Gα13 but also with Gαq. In cellular coimmunoprecipitation studies, the LARG RGS box formed stable complexes with the transition state mimetic forms of Gαq, Gα12, and Gα13. Expression of the LARG RGS box diminished the transforming activity of oncogenic G protein-coupled receptors (Mas, G2A, and ml-muscarinic cholinergic) coupled to Gαq and Gα13. Activated Gαq, as well as Gα12 and Gα13, cooperated with LARG and caused synergistic activation of RhoA, suggesting that all three Gα 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.
AB - 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 α subunits. p115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of Gα12/13 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 Gα subunits and couple Gα activation to RhoA-mediating signaling pathways. Unlike the RGS box of p115 RhoGEF, the RGS box of LARG interacts not only with Gα12 and Gα13 but also with Gαq. In cellular coimmunoprecipitation studies, the LARG RGS box formed stable complexes with the transition state mimetic forms of Gαq, Gα12, and Gα13. Expression of the LARG RGS box diminished the transforming activity of oncogenic G protein-coupled receptors (Mas, G2A, and ml-muscarinic cholinergic) coupled to Gαq and Gα13. Activated Gαq, as well as Gα12 and Gα13, cooperated with LARG and caused synergistic activation of RhoA, suggesting that all three Gα 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.
UR - http://www.scopus.com/inward/record.url?scp=0036261720&partnerID=8YFLogxK
U2 - 10.1128/MCB.22.12.4053-4061.2002
DO - 10.1128/MCB.22.12.4053-4061.2002
M3 - Article
C2 - 12024019
AN - SCOPUS:0036261720
SN - 0270-7306
VL - 22
SP - 4053
EP - 4061
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 12
ER -