TC10, a mammalian Rho GTPase responsible for actin cytoskeleton reorganization and cardiac hypertrophy in the murine heart

Abstract

Rho guanosine triphosphatases (GTPases) act as molecular switches, cycling between two conformational states: an active, GTP-bound state and an inactive, GDP-bound state to control many complex cellular events in eukaryotic cells. Many Rho GTPases, including RhoA, Cdc42 and Rac1, have been extensively characterized and are involved in actin reorganization, activation of MAPK cascades, cell cycle progression, cellular proliferation, invasion, differentiation and apoptosis. TC10 was identified and classified as a Rho GTPase over ten years ago, however the precise role of this protein, which is highly expressed in cardiac and skeletal muscle, has only recently been explored in vitro and remains unexplored in vivo. Based on the unique expression pattern of TC10, we set out to investigate the role of TC10 by generating transgenic mice over-expressing activated TC10Q75L under the control of the cardiac-specific alpha-myosin heavy chain promoter. Transgenic mice expressing high levels of TC10Q75L showed pronounced atrial enlargement, evidence of left ventricular hypertrophy and diminished cardiomyocyte membrane integrity. In vitro, transgenic primary cardiomyocytes showed marked reorganization of the actin cytoskeleton, leading to the formation of actin-containing filopodial extensions, loss of stress fibers and actin aggregation. Together, these data suggest that TC10 functions to regulate cellular signalling to the actin cytoskeleton and processes associated with cell growth, leading to cardiac hypertrophy in TC10Q75L transgenic mice.