Metabolic control of Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated caspase-2 suppression by the B55β/protein phosphatase 2A (PP2A).
High levels of metabolic activity confer resistance to apoptosis. Caspase-2, an apoptotic initiator, can be suppressed by high levels of nutrient flux through the pentose phosphate pathway. This metabolic control is exerted via inhibitory phosphorylation of the caspase-2 prodomain by activated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). We show here that this activation of CaMKII depends, in part, on dephosphorylation of CaMKII at novel sites (Thr(393)/Ser(395)) and that this is mediated by metabolic activation of protein phosphatase 2A in complex with the B55β targeting subunit. This represents a novel locus of CaMKII control and also provides a mechanism contributing to metabolic control of apoptosis. These findings may have implications for metabolic control of the many CaMKII-controlled and protein phosphatase 2A-regulated physiological processes, because both enzymes appear to be responsive to alterations in glucose metabolized via the pentose phosphate pathway.
From the Department of Pharmacology and Cancer Biology.
Bofu
B
Huang
From the Department of Pharmacology and Cancer Biology.
Chih-Sheng
CS
Yang
From the Department of Pharmacology and Cancer Biology.
Jeffrey
J
Wojton
From the Department of Pharmacology and Cancer Biology.
Nai-Jia
NJ
Huang
From the Department of Pharmacology and Cancer Biology.
Chen
C
Chen
the Proteomics and Metabolomics Core Facility, and.
Erik J
EJ
Soderblom
the Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27705 liguo.zhang@duke.edu.
Liguo
L
Zhang
From the Department of Pharmacology and Cancer Biology, sally.kornbluth@duke.edu.
Sally
S
Kornbluth
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D053143:Caspase 2 / Q000378:metabolism*; D004789:Enzyme Activation; D019298:Glucose-6-Phosphate / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis
D029867:Xenopus Proteins; D019298:Glucose-6-Phosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054648:Protein Phosphatase 2; D053143:Caspase 2
Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII); Caspase 2; Metabolism; Mutagenesis; Phosphatase; Phosphorylation