Activation of atypical protein kinase C by sphingosine 1-phosphate revealed by an aPKC-specific activity reporter.

Atypical protein kinase C isozymes are unique in the superfamily in that they are not regulated by the lipid second messenger diacylglycerol, which has led to speculation about whether a different second messenger acutely controls their function. Here, using a genetically encoded reporter that we designed, C kinase activity reporter (aCKAR), we found that the lipid mediator sphingosine 1-phosphate (S1P) promoted the cellular activity of Intracellular S1P directly bound to the purified kinase domain of and relieved autoinhibitory constraints, thereby activating the kinase. In silico studies identified potential binding sites on the kinase domain, one of which was validated biochemically. In HeLa cells, S1P-dependent activation of aduanyu1531 suppressed apoptosis. Together, our findings identify a previously undescribed molecular mechanism of aduanyu1531 regulation, a molecular target for S1P in cell survival regulation, and a tool to further explore the biochemical and biological functions of

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