cGMP-dependent protein kinase I promotes cell apoptosis through hyperactivation of death-associated protein kinase 2

Biochem Biophys Res Commun. 2012 Jun 1;422(2):280-4. doi: 10.1016/j.bbrc.2012.04.148. Epub 2012 May 3.

Abstract

cGMP-dependent protein kinase-I (cGK-I) induces apoptosis in various cancer cell lines. However, the signaling mechanisms involved remain unknown. Using protein microarray technology, we identified a novel cGK substrate, death-associated protein kinase 2 (DAPK2), which is a Ca(2+)/calmodulin-regulated serine/threonine kinase. cGK-I phosphorylated DAPK2 at Ser(299), Ser(367) and Ser(368). Interestingly, a phospho-mimic mutant, DAPK2 S299D, significantly enhanced its kinase activity in the absence of Ca(2+)/calmodulin, while a S367D/S368D mutant did not. Overexpression of DAPK2 S299D also resulted in a twofold increase in apoptosis of human breast cancer MCF-7 cells as compared with wild-type DAPK2. These results suggest that DAPK2 is one of the targets of cGK-I in apoptosis induction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Apoptosis*
  • COS Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases / metabolism*
  • Death-Associated Protein Kinases
  • Enzyme Activation
  • Humans
  • Mice
  • Mutation
  • Phosphorylation
  • Protein Array Analysis
  • Serine / genetics
  • Serine / metabolism
  • Substrate Specificity

Substances

  • Apoptosis Regulatory Proteins
  • Serine
  • DAPK2 protein, human
  • Death-Associated Protein Kinases
  • dapk2 protein, mouse
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases
  • PRKG1 protein, human
  • Prkg1 protein, mouse
  • Calcium-Calmodulin-Dependent Protein Kinases