| 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 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.</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 B55β as a potential target for cancer therapy, because of its importance
in suppressing metabolic suppression of caspase-2 activation and apoptosis.</p>
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