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 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.
Obreztchikova
Maria
M
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Elouardighi
Hasnae
H
Ho
Mengfei
M
Wilson
Brenda A
BA
Gertsberg
Zoya
Z
Steinberg
Susan F
SF
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology; D006321:Heart / Q000254:growth & development / Q000502:physiology*; D032342:Muscle Cells / Q000166:cytology; D009206:Myocardium / Q000166:cytology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D020033:Protein Isoforms / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013917:Thrombin / Q000494:pharmacology; D015533:Transcriptional Activation
D048868:Adaptor Proteins, Signal Transducing; D020033:Protein Isoforms; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D010768:Phosphoserine; D066246:ErbB Receptors; D013917:Thrombin