Research ArticleBiochemistry

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

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Science Signaling  01 Jan 2019:
Vol. 12, Issue 562, eaat6662
DOI: 10.1126/scisignal.aat6662

Atypical activation of cell survival

The function and regulation of atypical protein kinase C (aPKC) isoforms are less well understood than those of the wider PKC family, and aPKCs are not activated by the same signals that activate conventional PKCs. Kajimoto et al. developed a live-cell imaging reporter to study aPKC activation mechanisms and discovered that basal pools of the lipid S1P bound to and activated aPKC by disrupting its autoinhibitory conformation. S1P-induced activation of aPKC suppressed apoptotic signals in various cell types. Given that both aPKC and S1P are individually associated with cancer, these findings reveal that the kinase and lipid are directly linked in a cell survival mechanism.


Atypical protein kinase C (aPKC) isozymes are unique in the PKC 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, aPKC-specific C kinase activity reporter (aCKAR), we found that the lipid mediator sphingosine 1-phosphate (S1P) promoted the cellular activity of aPKC. Intracellular S1P directly bound to the purified kinase domain of aPKC 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 aPKC suppressed apoptosis. Together, our findings identify a previously undescribed molecular mechanism of aPKC regulation, a molecular target for S1P in cell survival regulation, and a tool to further explore the biochemical and biological functions of aPKC.

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