Regulation of gene expression by the small GTPase Rho through the ERK6 (p38 gamma) MAP kinase pathway

Small GTP-binding proteins of the Rho-family, Rho, pac, and Cdc42, have bee n traditionally linked to the regulation of the cellular actin-based cytosk eleton. Rac and Cdc42 can also control the activity of INK, thus acting in a molecular pathway transmitting extracellular signals to the nucleus. Inte restingly, Rho can also regulate gene expression, albeit by a not fully und erstood mechanism. Here, we found that activated RhoA can stimulate c-jun e xpression and the activity of the c-jun promoter. As the complexity of the signaling pathways controlling the expression of c-jun has begun to be unra veled, this finding provided a unique opportunity to elucidate the biochemi cal routes whereby RhoA regulates nuclear events. We found that RhoA can in itiate a linear kinase cascade leading to the activation of ERK6 (p38 gamma ), a recently identified member of the p38 family of MAPKs. Furthermore, we present evidence that RhoA, PKN, MKK3/MKK6, and ERK6 (p38 gamma) are compo nents of a novel signal transduction pathway involved in the regulation of gene expression and cellular transformation.