Protein phosphatase 2A (PP2A) holoenzymes regulate death-associated protein kinase (DAPK) in ceramide-induced anoikis.

Widau RC, Jin Y, Dixon SA, Wadzinski BE, Gallagher PJ
J Biol Chem. 2010 285 (18): 13827-38

PMID: 20220139 · PMCID: PMC2859546 · DOI:10.1074/jbc.M109.085076

The tumor suppressor, death-associated protein kinase (DAPK), is a Ca(2+)/calmodulin-regulated Ser/Thr kinase with an important role in regulating cytoskeletal dynamics. Autophosphorylation within the calmodulin-binding domain at Ser-308 inhibits DAPK catalytic activity. Dephosphorylation of Ser-308 by a previously unknown phosphatase enhances kinase activity and proteasome-mediated degradation of DAPK. In these studies, we identified two holoenzyme forms of protein phosphatase 2A (PP2A), ABalphaC and ABdeltaC, as DAPK-interacting proteins. These phosphatase holoenzymes dephosphorylate DAPK at Ser-308 in vitro and in vivo resulting in enhanced kinase activity of DAPK. The enzymatic activity of PP2A also negatively regulates DAPK levels by enhancing proteasome-mediated degradation of the kinase. Overexpression of wild type DAPK induces cell rounding and detachment in HEK293 cells; however, this effect is not observed following expression of an inactive DAPK S308E mutant. Finally, activation of DAPK by PP2A was found to be required for ceramide-induced anoikis. Together, our results provide a mechanism by which PP2A and DAPK activities control cell adhesion and anoikis.

MeSH Terms (15)

Amino Acid Substitution Anoikis Apoptosis Regulatory Proteins Calcium-Calmodulin-Dependent Protein Kinases Cell Adhesion Ceramides Cytoskeleton Death-Associated Protein Kinases HeLa Cells Holoenzymes Humans Mutation, Missense Phosphorylation Protein Phosphatase 2 Tumor Suppressor Proteins

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