Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA

Rho-like GTPases play a pivotal role in the orchestration of changes in the actin cytoskeleton in response to receptor stimulation, and have been impl icated in transcriptional activation, cell growth regulation, and oncogenic transformation. Recently, a role for RhoA in the regulation of cardiac con tractility and hypertrophic cardiomyocyte growth has been suggested but the mechanisms underlying RhoA function in the heart remain undefined. We now report that transcription factor GATA-4, a key regulator of cardiac genes, is a nuclear mediator of RhoA signaling and is involved in the control of s arcomere assembly in cardiomyocytes. Both RhoA and GATA-4 are essential for sarcomeric reorganization in response to hypertrophic growth stimuli and o verexpression of either protein is sufficient to induce sarcomeric reorgani zation. Consistent with convergence of RhoA and GATA signaling RhoA potenti ates the transcriptional activity of GATA-4 via a p38 MAPK-dependent pathwa y that phosphorylates GATA-4 activation domains and GATA binding sites medi ate RhoA activation of target cardiac promoters. Moreover, a dominant-negat ive GATA-4 protein abolishes RhoA-induced sarcomere reorganization. The ide ntification of transcription factor GATA-4 as a RhoA mediator in sarcomere reorganization and cardiac gene regulation provides a link between RhoA eff ects on transcription and cell remodeling.