The Rho GAP RRC-1 is required for the assembly or stability of integrin adhesion complexes and is a member of the PIX pathway in muscle

Abstract

GTPases cycle between active GTP bound and inactive GDP bound forms. Exchange of GDP for GTP is catalyzed by guanine nucleotide exchange factors (GEFs). GTPase activating proteins (GAPs) accelerate GTP hydrolysis, to promote the GDP bound form. Recently, we reported that the GEF called PIX is required for assembly or stability of integrin adhesion complexes (IAC) in striated muscle. A GAP for the PIX pathway had not been identified in any cell type or organism. A screen in C. elegans of mutants in 18 proteins containing Rho GAP domains and expressed in muscle revealed that loss of function of rrc-1 results in loss of IAC components at the muscle cell boundary (MCB). RRC-1 contains an SH3 domain and a Rho GAP domain, and is localized to the IACs of MCBs, like PIX-1. rrc-1 mutants show reduced accumulation of IAC components at the MCB, sarcomere disorganization, and reduced whole animal locomotion. Knockdown of git-1, which encodes a PIX scaffold protein, reduces the level of RRC-1. Localization at MCBs of RRC-1 depends on pix-1, and the localization of PIX-1 depends on rrc-1. These results suggest that RRC-1 is a RhoGAP for the PIX pathway in muscle.