title: Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle.
abstract: Akt/PKB is a key signaling molecule in higher eukaryotes and a crucial protein kinase in human health and disease. Phosphorylation, acetylation, and ubiquitylation have been reported as important regulatory post-translational modifications of this kinase. We describe here that Akt is modified by SUMO conjugation, and show that lysine residues 276 and 301 are the major SUMO attachment sites within this protein. We found that phosphorylation and SUMOylation of Akt appear as independent events. However, decreasing Akt SUMOylation levels severely affects the role of this kinase as a regulator of fibronectin and Bcl-x alternative splicing. Moreover, we observed that the Akt mutant (Akt E17K) found in several human tumors displays increased levels of SUMOylation and also an enhanced capacity to regulate fibronectin splicing patterns. This splicing regulatory activity is completely abolished by decreasing Akt E17K SUMO conjugation levels. Additionally, we found that SUMOylation controls Akt regulatory function at G₁/S transition during cell cycle progression. These findings reveal SUMO conjugation as a novel level of regulation for Akt activity, opening new areas of exploration related to the molecular mechanisms involved in the diverse cellular functions of this kinase.
authors.affiliation: Instituto de Fisiología, Biología Molecular y Neurociencias-Consejo Nacional de Investigaciones Científicas y Técnicas; Departamento de Fisiología, Biología Molecular y Celular; Facultad de Ciencias Exactas y Naturales-Universidad de Buenos Aires; Buenos Aires, Argentina.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Risso
authors.forename: Federico
authors.initials: F
authors.lastname: Pelisch
authors.forename: Berta
authors.initials: B
authors.lastname: Pozzi
authors.forename: Pablo
authors.initials: P
authors.lastname: Mammi
authors.forename: Matías
authors.initials: M
authors.lastname: Blaustein
authors.forename: Alejandro
authors.initials: A
authors.lastname: Colman-Lerner
authors.forename: Anabella
authors.initials: A
authors.lastname: Srebrow
mesh_terms: D017398:Alternative Splicing; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D058207:Sumoylation; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D005353:Fibronectins; D034741:RNA, Small Interfering; D025841:Small Ubiquitin-Related Modifier Proteins; D051020:bcl-X Protein; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt/PKB; SUMO; alternative splicing; cell cycle; post-translational modification; signal transduction