Work

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

Year: 2019

Type: article

Abstract: 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.

Source: Science Signaling

DOI: 10.1126/scisignal.aat6662

Authors: Taketoshi Kajimoto, Alisha D. Caliman, Irene S. Tobias, Taro Okada, Caila A. Pilo, An-Angela N. Van, J. Andrew McCammon, Shun-ichi Nakamura, Alexandra C. Newton

Institutions: University of California San Diego, Kobe University

Language: English

Topic: Sphingolipid Metabolism and Signaling

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering, Japan Society for the Promotion of Science, NIH Office of the Director, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases

Awards: Involvement of S1P receptor signaling and exosome release on Parkinson's disease, G2300512374, PKA & PKC Targeting Mechanisms (Program Project), G281299700, G2864509162, Studies on the coupling mechanism between lysobisphosphatidic acid (LBPA) and S1P signaling, Clarification of the mechanism of S1P-signaling-induced exosome maturation on tumor-promoting inflammation, G4249372741, Inhibition of S1P receptor signal transduction by extracellular alpha-synuclein, Graduate Training in Cellular and Molecular Pharmacology, G5622224354, Role of sphingosine 1-phosphate signaling on tumor metastasis, Clarification of the mechanism of cancer metastasis by sphingosine 1-phosphate signaling(Fostering Joint International Research), G7080814666, Theory of Biomolecular Diffusion, NATIONAL BIOMEDICAL COMPUTATION RESOURCE, G8589498581, G8993347806, Molecular Mechanisms of Cell Signaling

OpenAlex ID: W2906934439

FWCI: 1.967

Cites: 70

Cited by: 49

Related to: 10