Activation of atypical protein kinase C by sphingosine 1-phosphate revealed by an aPKC-specific activity reporter
| Autor: | Caila A. Pilo, An-Angela N. Van, Taro Okada, Alisha D. Caliman, J. Andrew McCammon, Alexandra C. Newton, Taketoshi Kajimoto, Shun-ichi Nakamura, Irene S. Tobias |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Sphingosine Chemistry Kinase Cell Biology Lipid signaling Biochemistry Cell biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein kinase domain Second messenger system lipids (amino acids peptides and proteins) Kinase activity Molecular Biology 030217 neurology & neurosurgery Protein kinase C 030304 developmental biology Diacylglycerol kinase |
| Zdroj: | Science Signaling. 12 |
| ISSN: | 1937-9145 1945-0877 |
| DOI: | 10.1126/scisignal.aat6662 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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