Metabolic Control of CaMKII-mediated Caspase-2 Suppression by B55β/PP2A

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Huang, Bofu


Kornbluth, Sally

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Apoptosis is a programmed form of cell death, essential for maintaining tissue homeostasis and eliminating dysfunctional cells. The process of apoptosis is executed by a family of cysteine proteases called caspases. 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 (PPP). This metabolic suppression of caspase-2 is exerted via the inhibitory phosphorylation of S135 on the caspase-2 prodomain by activated Ca2+/Calmodulin-dependent protein kinase II (CaMKII). However, it was unclear how CaMKII activity is regulated by nutrient flux.

After investigating how nutrient flux leads to activation of CaMKII, a recent study reported that coenzyme A (CoA) can directly bind to and activate CaMKII. However, by performing mass spectrometry (MS) analysis of CaMKII, and other biochemical assays, including gel filtration assays, immuno-precipitation assays, immuno-depletion assays, and in vitro kinase assays, in the Xenopus egg extract system, our studies show that the complete nutrient-driven CaMKII activation requires the additional release of a "brake" through the dephosphorylation of CaMKII at novel sites (T393/S395). Furthermore, this metabolically-stimulated dephosphorylation of CaMKII is mediated by the metabolic activation of protein phosphatase 2A (PP2A) in complex with the B55β targeting subunit. Importantly, our findings have been successfully replicated in human 293T cells, including the metabolic activation of CaMKII, and also the suppression of this activation by B55β knockdown.

Our discovery represents a novel locus of CaMKII regulation 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 PP2A-regulated physiological processes, as both enzymes appear to be responsive to alterations in glucose metabolized via the PPP. Finally, our study reveals B55β as a potential target for cancer therapy, because of its importance in suppressing metabolic suppression of caspase-2 activation and apoptosis.






Huang, Bofu (2015). Metabolic Control of CaMKII-mediated Caspase-2 Suppression by B55β/PP2A. Dissertation, Duke University. Retrieved from


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