期刊
FASEB JOURNAL
卷 33, 期 8, 页码 9044-9061出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201800490RR
关键词
oncology; protein-protein interaction; kinase; RNA editing; nucleus
资金
- Leukemia Research Foundation
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [17137, 17615]
- Del Monte Foundation
- Intesa San Paolo Foundation
- Italian Ministero dell'Istruzione dell'Universita' e della Ricerca-Progetti di Rilevante Interesse Nazionale (MIUR-PRIN)
- 5 X 1000 fund of the Rizzoli Orthopedic Institute
Murine thymoma viral oncogene homolog (AKT) kinases target both cytosolic and nuclear substrates for phosphorylation. Whereas the cytosolic substrates are known to be closely associated with the regulation of apoptosis and autophagy or metabolism and protein synthesis, the nuclear substrates are, for the most part, poorly understood. To better define the role of nuclear AKT, potential AKT substrates were isolated from the nuclear lysates of leukemic cell lines using a phosphorylated AKT substrate antibody and identified in tandem mass spectrometry. Among the proteins identified was adenosine deaminase acting on RNA (ADAR)1p110, the predominant nuclear isoform of the adenosine deaminase acting on double-stranded RNA. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively, and overexpression of the phosphomimic mutants ADAR1p110 (T738D) and ADAR2 (T553D) resulted in a 50-100% reduction in editase activity. Thus, activation of AKT has a direct and major impact on RNA editing.-Bavelloni, A., Focaccia, E., Piazzi, M., Raffini, M., Cesarini, V., Tomaselli, S., Orsini, A., Ratti, S., Faenza, I., Cocco, L., Gallo, A., Blalock, W. L. AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity.
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