PKC-α and TAK-1 are intermediates in the activation of c-Jun NH 2-terminal kinase by hypoxia-reoxygenation

Donna P. Frazier, Amber Wilson, Christopher J. Dougherty, Huifang Li, Nanette H. Bishopric, Keith A. Webster

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

c-Jun NH2-terminal kinase (JNK), a member of the MAPK family of protein kinases, is a stress-response kinase that is activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through nonreceptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We recently demonstrated that the activation of JNK by this condition is initiated by ROI generated by mitochondrial electron transport and involves sequential activation of the proline-rich kinase 2 and the small GTP-binding factors Rac-1 and Cdc42. Here we present evidence that protein kinase C (PKC) and transforming growth factor-β-activated kinase-1 (TAK-1) are also components of this pathway. Inhibition of PKC with the broad-range inhibitor calphostin C, the PKC-α/β-selective inhibitor Go9367, or adenovirus-expressing dominant-negative PKC-α blocked the phosphorylation of proline-rich kinase 2 and JNK. Reoxygenation activated the mitogen-activated protein kinase kinase kinase, TAK-1, and promoted the formation of a complex containing Rac-1, TAK-1, and JNK but not apoptosis-stimulating kinase-1 or p21-activated kinase-1, which was detected within the first 10 min of reoxygenation. These results identify two new components, PKC and TAK-1, that have not been previously described in this signaling pathway.

Original languageEnglish (US)
Pages (from-to)H1675-H1684
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume292
Issue number4
DOIs
StatePublished - Apr 1 2007

Keywords

  • Cardiac myocyte
  • Hydrogen peroxide
  • Mitochondria
  • Proline-rich tyrosine kinase 2
  • Protein kinase C
  • Transforming growth factor-β-activated kinase-1

ASJC Scopus subject areas

  • Physiology

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