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 Tyr(239)/Tyr(240) and Tyr(317) (and p66Shc-Ser(36) phosphorylation) via a
pertussis toxin-insensitive
epidermal growth factor receptor (EGFR) transactivation pathway in cardiac fibroblasts; p66Shc-Ser(36) phosphorylation is via a
MEK-dependent mechanism. In contrast, cardiac fibroblasts express beta(2)-adrenergic receptors that activate ERK through a
pertussis toxin-sensitive EGFR transactivation pathway that does not involve Shc
isoforms or lead to p66Shc-Ser(36) phosphorylation. In cardiomyocytes,
thrombin triggers
MEK-dependent p66Shc-Ser(36) phosphorylation, but this is not via EGFR transactivation (or associated with Shc-Tyr(239)/Tyr(240) and/or Tyr(317) 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 Galpha(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 Galpha(q) agonist and that PAR-1 activation leads to p66Shc-Ser(36) phosphorylation identifies p66Shc as a novel candidate
hypertrophy-induced mediator of cardiomyocyte apoptosis and
heart failure.