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.

Disruption of c-Jun Reduces Cellular Migration and Invasion through Inhibition of c-Src and Hyperactivation of ROCK II Kinase

“…In our studies, c-Jun reintroduction into c-jun Ϫ/Ϫ cells inhibited Rho kinase activity and induced cellular migration. Silenc- (Marinissen et al, 2004). Endogenous c-Jun-mediated inhibition of c-Src expression would be predicted to function in a homeostatic feedback to normalize c-Jun induction by ROCK.…”

“…ROCK activates JNK, which phosphorylates c-Jun and ATF2, to induce c-Jun expression (Marinissen et al, 2004). RhoA stimulation of ROCK occurs independently of the ability of ROCK to promote actin polymerization.…”

CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells

“…[25][26][27][28]. Twenty-four hours after seeding, the cells were transiently transfected in triplicate with reporters together with pRL-null, a plasmid expressing the enzyme Renilla luciferase, used as an internal control (Promega Corporation).…”

“…We analyzed the capability of a GFP-tagged CD44-ICD construct to trans-activate a panel of promoter elements, including AP-1 (activating protein-1), SRF (serum response factor), TCF (ternary complex factor), Gli (Glioma-associated oncogene homolog), NF-kB, and CRE (cAMP-responsive element) reporters (25)(26)(27)(28). CD44-ICD strongly (about 10-fold, P < 0.01) activated the CRE reporter in HEK293T cells, but not the other promoters (Fig.…”

Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases

“…Another important question that has not been addressed is a comprehensive study of the effect of these GTPases on gene transcription at the genome-wide level. Thus, despite evidence showing that Rho subfamily proteins can activate transcriptional factors such as nuclear-factor kappa B (NF-kB), the serum response factor (SRF) or AP1 family proteins (Hill et al, 1995;Perona et al, 1997;Montaner et al, 1998Montaner et al, , 1999Marinissen et al, 2004;Wheeler and Ridley, 2004;Jaffe and Hall, 2005), there is only scarce information regarding the effect of Rho subfamily proteins and their main effectors in the overall cell transcriptome. Indeed, to date, there are only two microarray-based studies available using either RhoA or RhoC oncoproteins in NIH3T3 and MCF10A cells (Teramoto et al, 2003;Wu et al, 2004), respectively.…”