P62 binding to protein kinase C ζ regulates tumor necrosis factor α-induced apoptotic pathway in endothelial cells

Geun Young Kim, Patrizia Nigro, Keigi Fujiwara, Jun Ichi Abe, Bradford C. Berk

Research output: Contribution to journalArticle

Abstract

OBJECTIVE-: Protein kinase C (PKC) ζ is a key pathological mediator of endothelial cell apoptosis. p62 is a scaffold protein that regulates several cell signaling pathways by binding to target proteins. Because PKCζ and p62 contain Phox/Bem1p (PB1) modules that mediate protein-protein interactions, we hypothesized that an interaction between p62 and PKCζ is required for tumor necrosis factor α-induced PKCζ signaling in endothelial cells. METHODS AND RESULTS-: In human umbilical vein endothelial cell, tumor necrosis factor α (10 ng/mL) enhanced the interaction between p62 and PKCζ. Transfection with p62 small interfering RNA reduced the activation of both PKCζ and its downstream targets JNK and caspase 3, suggesting that p62 is necessary for PKCζ signaling. Overexpression of only the PB1 domain of p62 inhibited p62-PKCζ interaction, showing that binding of these 2 proteins is mediated by their PB1 domains. Furthermore, overexpression of the p62 PB1 domain suppressed tumor necrosis factor α-induced PKCζ activation and subsequent activation of JNK and caspase 3. Finally, transfection of either p62 small interfering RNA or the PB1 domain of p62 inhibited human umbilical vein endothelial cell apoptosis. CONCLUSION-: Our results suggest a novel function of p62 that regulates the activity of PKCζ by binding to PKCζ, thereby activating the PKCζ-JNK-caspase 3 apoptotic pathway in endothelial cells.

Original languageEnglish
Pages (from-to)2974-2980
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number12
DOIs
Publication statusPublished - Dec 2012

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Keywords

  • apoptosis
  • endothelial cells
  • p62
  • Phox/Bem1p domain
  • protein kinase Cζ

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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