Huang Bofu, Yang Chih-Sheng, Wojton Jeffrey, Huang Nai-Jia, Chen Chen, Soderblom Erik J, Zhang Liguo, Kornbluth Sally
From the Department of Pharmacology and Cancer Biology.
the Proteomics and Metabolomics Core Facility, and.
J Biol Chem. 2014 Dec 26;289(52):35882-90. doi: 10.1074/jbc.M114.585844. Epub 2014 Nov 4.
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.
高水平的代谢活性赋予细胞对凋亡的抗性。凋亡起始因子半胱天冬酶-2（Caspase-2）可被通过磷酸戊糖途径的高水平营养物质通量所抑制。这种代谢调控是通过活化的钙/钙调蛋白依赖性蛋白激酶II（CaMKII）对Caspase-2前结构域的抑制性磷酸化来实现的。我们在此表明，CaMKII的这种激活部分取决于其在新位点（苏氨酸393/丝氨酸395）的去磷酸化，并且这是由与B55β靶向亚基结合的蛋白磷酸酶2A的代谢激活介导的。这代表了CaMKII调控的一个新位点，也提供了一种有助于凋亡代谢调控的机制。这些发现可能对许多由CaMKII控制和蛋白磷酸酶2A调节的生理过程的代谢调控有影响，因为这两种酶似乎都对通过磷酸戊糖途径代谢的葡萄糖变化有反应。
