AHEART June 47/6

Wei, Lei, Wei Zhou, Lu Wang, and Robert J. Schwartz. b1-Integrin and PI 3-kinase regulate RhoA-dependent activation of skeletal a-actin promoter in myoblasts. Am J Physiol Heart Circ Physiol 278: H1736–H1743, 2000.—RhoA GTPase, a regulator of actin cytoskeleton, is also involved in regulating c-fos gene expression through its effect on serum response factor (SRF) transcriptional activity. We have also shown that RhoA plays a critical role in myogenesis and regulates expression of SRF-dependent muscle genes, including skeletal a-actin. In the present study, we examined whether the RhoA signaling pathway cross talks with other myogenic signaling pathways to modulate skeletal a-actin promoter activity in myoblasts. We found that extracellular matrix proteins and the b1-integrin stimulated RhoA-dependent activation of the a-actin promoter. The muscle-specific isoform b1D selectively activated the a-actin promoter in concert with RhoA but inhibited the c-fos promoter. In addition, focal adhesion kinase (FAK) and phosphatidylinositol (PI) 3-kinase were required for full activation of the a-actin promoter by RhoA. Expression of a dominant negative mutant of FAK, application of wortmannin to cultured myoblasts, or expression of a dominant negative mutant of PI 3-kinase inhibited a-actin promoter activity induced by RhoA. These results suggest that RhoA, b1-integrin, FAK, and PI 3-kinase serve together as an important signaling network in regulating muscle gene expression.