Dual Site Phosphorylation of Caspase-7 by PAK2 Blocks Apoptotic Activity by Two Distinct Mechanisms

Structure. 2017 Jan 3;25(1):27-39. doi: 10.1016/j.str.2016.11.001. Epub 2016 Nov 23.

Abstract

Caspases, the cysteine proteases that execute apoptosis, are tightly regulated via phosphorylation by a series of kinases. Although all apoptotic caspases work in concert to promote apoptosis, different kinases regulate individual caspases. Several sites of caspase-7 phosphorylation have been reported, but without knowing the molecular details, it has been impossible to exploit or control these complex interactions, which normally prevent unwanted proliferation. During dysregulation, PAK2 kinase plays an alternative anti-apoptotic role, phosphorylating caspase-7 and promoting unfettered cell growth and chemotherapeutic resistance. PAK2 phosphorylates caspase-7 at two sites, inhibiting activity using two different molecular mechanisms, before and during apoptosis. Phosphorylation of caspase-7 S30 allosterically obstructs its interaction with caspase-9, preventing intersubunit linker processing, slowing or preventing caspase-7 activation. S239 phosphorylation renders active caspase-7 incapable of binding substrate, blocking later events in apoptosis. Each of these mechanisms is novel, representing new opportunities for synergistic control of caspases and their counterpart kinases.

Keywords: apoptosis; caspase; cysteine protease; kinase; kinase-caspase interaction; phosphomimetic; phosphorylation; phosphorylation-mediated inhibition; prodomain; steric block at active site.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis
  • Binding Sites
  • Caspase 7 / chemistry*
  • Caspase 7 / metabolism*
  • Caspase 9 / metabolism
  • Cell Proliferation
  • Crystallography, X-Ray
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Humans
  • MCF-7 Cells
  • Models, Molecular
  • Neoplasms / metabolism*
  • Phosphorylation
  • Serine / metabolism*
  • p21-Activated Kinases / metabolism*

Substances

  • Serine
  • PAK2 protein, human
  • p21-Activated Kinases
  • CASP7 protein, human
  • CASP9 protein, human
  • Caspase 7
  • Caspase 9