Distinct signaling functions for Shc isoforms in the heart

Thrombin activates protease-activated receptor-1 (PAR-1) and engages signaling pathways that influence the growth and survival of cardiomyocytes as well as extracellular matrix remodeling by cardiac fibroblasts. This study examines the role of Shc proteins in PAR-1-dependent signaling pathways that influence ventricular remodeling. We show that thrombin increases p46Shc/p52Shc phosphorylation at Tyr²³⁹/Tyr²⁴⁰ and Tyr³¹⁷ (and p66Shc-Ser³⁶ phosphorylation) via a pertussis toxin-insensitive epidermal growth factor receptor (EGFR) transactivation pathway in cardiac fibroblasts; p66Shc-Ser³⁶ phosphorylation is via a MEK-dependent mechanism. In contrast, cardiac fibroblasts express β₂- adrenergic receptors that activate ERK through a pertussis toxin-sensitive EGFR transactivation pathway that does not involve Shc isoforms or lead to p66Shc-Ser³⁶ phosphorylation. In cardiomyocytes, thrombin triggers MEK-dependent p66Shc-Ser³⁶ phosphorylation, but this is not via EGFR transactivation (or associated with Shc-Tyr²³⁹/Tyr²⁴⁰ and/or Tyr³¹⁷ phosphorylation). Importantly, p66Shc protein expression is detected in neonatal, but not adult, cardiomyocytes; p66Shc expression is induced (via a mechanism that requires protein kinase C and MEK activity) by Pasteurella multocida toxin, a Gα_q agonist that promotes cardiomyocyte hypertrophy. These results identify novel regulation of individual Shc isoforms in receptor-dependent pathways leading to cardiac hypertrophy and the transition to heart failure. The observations that p66Shc expression is induced by a Gα_q agonist and that PAR-1 activation leads to p66Shc-Ser³⁶ phosphorylation identifies p66Shc as a novel candidate hypertrophy-induced mediator of cardiomyocyte apoptosis and heart failure.