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Published online 13 December 2004. doi:10.1083/jcb.200402033
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 6, 1147-1159
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Article

 Muscle ring finger protein-1 inhibits PKC{epsilon} activation and prevents cardiomyocyte hypertrophy

Ranjana Arya1, Vishram Kedar1, Jae Ryoung Hwang1, Holly McDonough1, Hui-Hua Li1, Joan Taylor5, and Cam Patterson1,2,3,4

1 Carolina Cardiovascular Biology Center,2 Department of Medicine,3 Department of Pharmacology,4 Department of Cell and Developmental Biology,5 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599

Correspondence to Cam Patterson: cpatters{at}med.unc.edu

Much effort has focused on characterizing the signal transduction cascades that are associated with cardiac hypertrophy. In spite of this, we still know little about the mechanisms that inhibit hypertrophic growth. We define a novel anti-hypertrophic signaling pathway regulated by muscle ring finger protein-1 (MURF1) that inhibits the agonist-stimulated PKC-mediated signaling response in neonatal rat ventricular myocytes. MURF1 interacts with receptor for activated protein kinase C (RACK1) and colocalizes with RACK1 after activation with phenylephrine or PMA. Coincident with this agonist-stimulated interaction, MURF1 blocks PKC{epsilon} translocation to focal adhesions, which is a critical event in the hypertrophic signaling cascade. MURF1 inhibits focal adhesion formation, and the activity of downstream effector ERK1/2 is also inhibited in the presence of MURF1. MURF1 inhibits phenylephrine-induced (but not IGF-1–induced) increases in cell size. These findings establish that MURF1 is a key regulator of the PKC-dependent hypertrophic response and can blunt cardiomyocyte hypertrophy, which may have important implications in the pathophysiology of clinical cardiac hypertrophy.

Abbreviations used in this paper: {alpha}-AR, {alpha}-adrenergic receptor; ANF, atrial natriuretic factor; IGF-1, insulin-like growth factor 1; MURF, muscle ring finger protein; NRVM, neonatal rat ventricular myocytes; PE, phenylephrine; RACK, receptor for activated protein kinase C; siRNA, small interfering RNA.


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