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

dc.contributor.advisor Kornbluth, Sally
dc.contributor.author Huang, Bofu
dc.date.accessioned 2015-05-12T20:44:22Z
dc.date.available 2017-04-08T04:30:04Z
dc.date.issued 2015
dc.identifier.uri http://hdl.handle.net/10161/9833
dc.description.abstract <p>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.</p><p>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 B55&#946; 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 B55&#946; knockdown.</p><p>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 B55&#946; as a potential target for cancer therapy, because of its importance in suppressing metabolic suppression of caspase-2 activation and apoptosis.</p>
dc.subject Biology
dc.subject Biochemistry
dc.subject CaMKII
dc.subject caspase-2
dc.subject metabolism
dc.subject phosphatase
dc.subject phosphorylation
dc.title Metabolic Control of CaMKII-mediated Caspase-2 Suppression by B55&#946;/PP2A
dc.type Dissertation
dc.department Pharmacology
duke.embargo.months 23


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