title: SUMO modification of Akt regulates global SUMOylation and substrate SUMOylation specificity through Akt phosphorylation of Ubc9 and SUMO1.
abstract: SUMOylation is an important post-translational modification, and Akt SUMOylation was found to regulate cell proliferation, tumorigenesis and cell cycle, but the molecular mechanism of Akt SUMOylation is less well known. Here, we show both endogenous and ectopic Akt SUMOylation and Lys276 is the major SUMO acceptor on Akt. Further, Akt SUMOylation is Akt phosphorylation dependent and Akt SUMOylation increases Akt kinase activity without affecting the phosphorylation level of Akt. Moreover, endogenous Akt SUMOylation is enhanced by insulin treatment and this is Akt activity dependent. Heat-shock stimulus also increases Akt SUMOylation and it is also Akt activity dependent. Endogenous Akt SUMOylation is also found in the rat brain and it is enhanced by insulin-like growth factor-1 stimulation. In addition, Akt directly phosphorylates Ubc9 at Thr35 and phosphorylates SUMO1 at Thr76. Ubc9 phosphorylation at Thr35 promotes Ubc9 thioester bond formation and SUMO1 phosphorylation at Thr76 stabilizes the SUMO1 protein. Through these distinct mechanisms, Akt SUMOylation regulates global SUMOylation, including Akt and Ubc9 SUMOylation, and substrate SUMOylation specificity, including STAT1 and CREB SUMOylation, in different manners. Akt SUMOylation also enhances phosphatase and tensin homolog (PTEN) SUMOylation through Akt phosphorylation of Ubc9 and SUMO1, which serves as an endogenous mechanism to stop the positive feedback loop resulted from Akt activation. Further, Akt SUMOylation increases cyclin D1 expression and cell proliferation, and these effects are also mediated through Ubc9 phosphorylation at Thr35 and SUMO1 phosphorylation at Thr76. Here, we have identified a novel mechanism for SUMOylation regulation. Because of the important role Akt plays in tumorigenesis, this mechanism may also be involved in Akt-regulated tumorigenesis.
authors: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: C H
authors: CH
authors: Lin
authors: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: S Y
authors: SY
authors: Liu
authors: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: E H Y
authors: EH
authors: Lee
mesh_terms: D049109:Cell Proliferation / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D013379:Substrate Specificity; D058207:Sumoylation; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D051057:Proto-Oncogene Proteins c-akt; D000098843:Ubiquitin-Conjugating Enzyme UBC9