Phospholipase Cε scaffolds to muscle-specific A kinase anchoring protein (mAKAPβ) and integrates multiple hypertrophic stimuli in cardiac myocytes

Lianghui Zhang, Sundeep Malik, Grant G. Kelley, Michael S Kapiloff, Alan V. Smrcka

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

To define a role for phospholipase Cε (PLCε) signaling in cardiac myocyte hypertrophic growth, PLCε protein was depleted from neonatal rat ventricular myocytes (NRVMs) using siRNA. NRVMs with PLCε depletion were stimulated with endothelin (ET-1), norepinephrine, insulin-like growth factor-1 (IGF-1), or isoproterenol and assessed for development of hypertrophy. PLCε depletion dramatically reduced hypertrophic growth and gene expression induced by all agonists tested. PLCε catalytic activity was required for hypertrophy development, yet PLCε depletion did not reduce global agonist-stimulated inositol phosphate production, suggesting a requirement for localized PLC activity. PLCε was found to be scaffolded to a muscle-specific A kinase anchoring protein (mAKAPβ) in heart and NRVMs, and mAKAPβ localizes to the nuclear envelope in NRVMs. PLCε-mAKAP interaction domains were defined and overexpressed to disrupt endogenous mAKAPβ-PLCε complexes in NRVMs, resulting in significantly reduced ET-1-dependent NRVM hypertrophy. We propose that PLCε integrates multiple upstream signaling pathways to generate local signals at the nucleus that regulate hypertrophy.

Original languageEnglish
Pages (from-to)23012-23021
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number26
DOIs
StatePublished - Jul 1 2011

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Type C Phospholipases
Cardiac Myocytes
Scaffolds
Protein Kinases
Muscle
Phosphotransferases
Muscles
Muscle Cells
Rats
Proteins
Hypertrophy
Protein Interaction Domains and Motifs
Inositol Phosphates
Endothelins
Nuclear Envelope
Endothelin-1
Somatomedins
Growth
Protein C
Isoproterenol

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Phospholipase Cε scaffolds to muscle-specific A kinase anchoring protein (mAKAPβ) and integrates multiple hypertrophic stimuli in cardiac myocytes. / Zhang, Lianghui; Malik, Sundeep; Kelley, Grant G.; Kapiloff, Michael S; Smrcka, Alan V.

In: Journal of Biological Chemistry, Vol. 286, No. 26, 01.07.2011, p. 23012-23021.

Research output: Contribution to journalArticle

Zhang, Lianghui ; Malik, Sundeep ; Kelley, Grant G. ; Kapiloff, Michael S ; Smrcka, Alan V. / Phospholipase Cε scaffolds to muscle-specific A kinase anchoring protein (mAKAPβ) and integrates multiple hypertrophic stimuli in cardiac myocytes. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 26. pp. 23012-23021.
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