Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes

Kai Mao, Satoru Kobayashi, Zahara M. Jaffer, Yuan Huang, Paul Volden, Jonathan Chernoff, Qiangrong Liang

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Akt/PKB is a critical regulator of cardiac function and morphology, and its activity is governed by dual phosphorylation at active loop (Thr308) by phosphoinositide-dependent protein kinase-1 (PDK1) and at carboxyl-terminal hydrophobic motif (Ser473) by a putative PDK2. P21-activated kinase-1 (Pak1) is a serine/threonine protein kinase implicated in the regulation of cardiac hypertrophy and contractility and was shown previously to activate Akt through an undefined mechanism. Here we report Pak1 as a potential PDK2 that is essential for Akt activity in cardiomyocytes. Both Pak1 and Akt can be activated by multiple hypertrophic stimuli or growth factors in a phosphatidylinositol-3-kinase (PI3K)-dependent manner. Pak1 overexpression induces Akt phosphorylation at both Ser473 and Thr308 in cardiomyocytes. Conversely, silencing or inactivating Pak1 gene diminishes Akt phosphorylation in vitro and in vivo. Purified Pak1 can directly phosphorylate Akt only at Ser473, suggesting that Pak1 may be a relevant PDK2 responsible for AKT Ser473 phosphorylation in cardiomyocytes. In addition, Pak1 protects cardiomyocytes from cell death, which is blocked by Akt inhibition. Our results connect two important regulators of cellular physiological functions and provide a potential mechanism for Pak1 signaling in cardiomyocytes.

Original languageEnglish (US)
Pages (from-to)429-434
Number of pages6
JournalJournal of Molecular and Cellular Cardiology
Volume44
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

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p21-Activated Kinases
Cardiac Myocytes
Phosphorylation
Phosphatidylinositol 3-Kinase
Protein-Serine-Threonine Kinases
Cardiomegaly
Phosphatidylinositols
Protein Kinases
Intercellular Signaling Peptides and Proteins
Cell Death

Keywords

  • Akt/PKB
  • Cardiomyocytes
  • P21-activated kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes. / Mao, Kai; Kobayashi, Satoru; Jaffer, Zahara M.; Huang, Yuan; Volden, Paul; Chernoff, Jonathan; Liang, Qiangrong.

In: Journal of Molecular and Cellular Cardiology, Vol. 44, No. 2, 02.2008, p. 429-434.

Research output: Contribution to journalArticle

Mao, K, Kobayashi, S, Jaffer, ZM, Huang, Y, Volden, P, Chernoff, J & Liang, Q 2008, 'Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes', Journal of Molecular and Cellular Cardiology, vol. 44, no. 2, pp. 429-434. https://doi.org/10.1016/j.yjmcc.2007.10.016
Mao, Kai ; Kobayashi, Satoru ; Jaffer, Zahara M. ; Huang, Yuan ; Volden, Paul ; Chernoff, Jonathan ; Liang, Qiangrong. / Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes. In: Journal of Molecular and Cellular Cardiology. 2008 ; Vol. 44, No. 2. pp. 429-434.
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