The Small GTP-Binding Protein RhoA Regulates c-Jun by a ROCK-JNK Signaling Axis

Abstract

RhoA regulates the actin cytoskeleton and the expression of genes associated with cell proliferation. This includes c-fos and c-jun, which are members of the AP1 family of transcription factors that play a key role in normal and aberrant cell growth. Whereas RhoA stimulates the c-fos SRE by a recently elucidated mechanism that is dependent on actin treadmilling, how RhoA regulates c-jun is still poorly understood. We found that RhoA stimulates c-jun expression through ROCK, but independently from the ability of ROCK to promote actin polymerization. Instead, we found that ROCK activates JNK, which then phosphorylates c-Jun and ATF2 when bound to the c-jun promoter. Thus, ROCK represents a point of signal divergence downstream from RhoA, as it promotes actin reorganization and the consequent expression from the c-fos SRE, while a parallel pathway connects ROCK to JNK, thereby stimulating c-jun expression. Ultimately, these pathways converge in the nucleus to regulate AP1 activity.