Distinct signaling functions for Shc isoforms in the heart

Maria Obreztchikova, Hasnae Elouardighi, Mengfei Ho, Brenda A. Wilson, Zoya Gertsberg, Susan F. Steinberg

Research output: Contribution to journalArticlepeer-review

Abstract

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 Gαq 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 Gαq 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.

Original languageEnglish (US)
Pages (from-to)20197-20204
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number29
DOIs
StatePublished - Jul 21 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Distinct signaling functions for Shc isoforms in the heart'. Together they form a unique fingerprint.

Cite this