Intracellular zinc increase affects phosphorylation state and subcellular localization of protein kinase C delta (δ)

Cell Signal. 2018 Apr;44:148-157. doi: 10.1016/j.cellsig.2018.01.018. Epub 2018 Feb 16.

Abstract

Protein kinase C delta (PKCδ) is a Ser/Thr-specific kinase involved in many fundamental cellular processes including growth, differentiation and apoptosis. PKCδ is expressed ubiquitously in all known cell types, and can be activated by diacylglycerol, phorbol esters and other kinases. Multiple lines of evidence have indicated that the mode of activation greatly influences the role PKCδ plays in cellular function. Divalent metal ions, such as zinc are released as a response to cellular stress and injury, often resulting in oxidative damage and cell death. In this study, we evaluate the effect increased concentrations of intracellular zinc has on the phosphorylation state and subcellular localization of PKCδ. More specifically, we demonstrate that intracellular zinc inhibits the phosphorylation of PKCδ at Thr505 in a concentration-dependent manner and facilitates the translocation of PKCδ from the cytosol to the Golgi complex. Analysis of a PKCδ structural model revealed a potential His-Cys3 zinc-binding domain adjacent to residue Thr505 and suggests that interaction with a Zn2+ ion may preclude phosphorylation at this site. This study establishes zinc as a potent modulator of PKCδ function and suggests a novel mechanism by which PKCδ is able to "sense" changes in the concentration of intracellular zinc. These findings illuminate a new paradigm of metal ion-protein interaction that may have significant implications on a broad spectrum of cellular processes.

Keywords: Intracellular zinc; Phosphorylation; Protein kinase C delta; Protein structure.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cytosol / metabolism
  • Golgi Apparatus / metabolism
  • HeLa Cells
  • Humans
  • Phosphorylation
  • Protein Kinase C-delta / metabolism*
  • Zinc / metabolism*

Substances

  • Protein Kinase C-delta
  • Zinc