Abstract
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.
Highlights
calmodulin-dependent protein kinase II (CaMKII) autophosphorylates at Thr286 in cell-free lysates supplemented with glucose-6-phosphate (G6P)
CaMKII Activity Is under Metabolic Control—As we reported previously, treatment of Xenopus egg extracts with G6P should elevate the kinase activity of CaMKII [9]
By directly treating egg extracts with or without G6P, we discovered that G6P increased phosphorylation of Thr286 on CaMKII, a known site of CaMKII autophosphorylation
Summary
CaMKII autophosphorylates at Thr286 in cell-free lysates supplemented with glucose-6-phosphate (G6P). 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 Ca2؉/calmodulin-dependent protein kinase II (CaMKII). We show here that this activation of CaMKII depends, in part, on dephosphorylation of CaMKII at novel sites (Thr393/Ser395) and that this is mediated by metabolic activation of protein phosphatase 2A in complex with the B55 targeting subunit. This represents a novel locus of CaMKII control and provides a mechanism contributing to metabolic control of apoptosis. These findings provide insight into metabolic control of apoptosis and define a new mechanism for controlling CaMKII, a protein critical for cell signaling in response to multiple stimuli
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
