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J. Biol. Chem., Vol. 278, Issue 13, 11714-11720, March 28, 2003
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From the Protease-activated receptor (PAR)-4 is a low
affinity thrombin receptor with slow activation and desensitization
kinetics relative to PAR-1. This study provides novel evidence that
cardiomyocytes express functional PAR-4 whose signaling phenotype is
distinct from PAR-1 in cardiomyocytes. AYPGKF, a modified PAR-4 agonist with increased potency at PAR-4, activates p38-mitogen-activated protein kinase but is a weak activator of phospholipase C,
extracellular signal-regulated kinase, and cardiomyocyte hypertrophy;
AYPGKF and thrombin, but not the PAR-1 agonist SFLLRN, activate Src. The observation that AYPGKF and thrombin activate Src in cardiomyocytes cultured from PAR-1
Mechanisms of Protease-activated Receptor-4 Actions in
Cardiomyocytes
ROLE OF Src TYROSINE KINASE*
§,,,
Departments of Pharmacology and Medicine,
College of Physicians and Surgeons, Columbia University, New York,
New York 10032 and ¶ Johnson and Johnson Pharmaceutical Research
and Development LLC, Spring House, Pennsylvania 19477
/ mice establishes that Src
activation is via PAR-4 (and not PAR-1) in cardiomyocytes. Further
studies implicate Src and epidermal growth factor receptor (EGFR)
kinase activity in the PAR-4-dependent p38-mitogen-activated protein kinase signaling pathway. Thrombin phosphorylates EGFRs and ErbB2 via a PP1-sensitive pathway in PAR-1/ cells that stably overexpress PAR-4; the
Src-mediated pathway for EGFR/ErbB2 transactivation underlies the
protracted phases of thrombin-dependent extracellular
signal-regulated kinase activation in PAR-1/ cells that
overexpress PAR-4 and in cardiomyocytes. These studies identify a
unique signaling phenotype for PAR-4 (relative to other cardiomyocyte G
protein-coupled receptors) that is predicted to contribute to cardiac
remodeling and influence the functional outcome at sites of cardiac inflammation.
*
This work was supported by United States Public Health
Service-NHLBI, National Institutes of Health Grant HL-64639.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Pharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168 St., New York, NY 10032. Tel.: 212-305-4297; Fax: 212-305-8780; E-mail: sfs1@columbia.edu.
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