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.
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References
Johnson ES . Protein modification by SUMO. Annu Rev Biochem 2004; 73: 355–382.
Hay RT . SUMO: a history of modification. Mol Cell 2005; 18: 1–12.
Pichler A, Gast A, Seeler JS, Dejean A, Melchior F . The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 2002; 108: 109–120.
Kagey MH, Melhuish TA, Wotton D . The polycomb protein Pc2 is a SUMO E3. Cell 2003; 113: 127–137.
Schmidt D, Muller S . PIAS/SUMO: new partners in transcriptional regulation. Cell Mol Life Sci 2003; 60: 2561–2574.
Gareau JR, Lima CD . The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 2010; 11: 861–871.
Tai DJC, Hsu WL, Liu YC, Ma YL . Lee EHY. Novel role and mechanism of protein inhibitor of activated STAT1 in spatial learning. EMBO J 2011; 30: 205–220.
Chen YC, Hsu WL, Ma YL, Tai DJ, Lee EH . CREB SUMOylation by the E3 ligase PIAS1 enhances spatial memory. J Neurosci 2014; 34: 9574–9589.
Chiou HY, Liu SY, Lin CH, Lee EH . Hes-1 SUMOylation by protein inhibitor of activated STAT1 enhances the suppressing effect of Hes-1 on GADD45alpha expression to increase cell survival. J Biomed Sci 2014; 21: 53–75.
Liao Y, Hung MC . Physiological regulation of Akt activity and stability. Am J Transl Res 2010; 2: 19–42.
Manning BD, Cantley LC . AKT/PKB signaling: navigating downstream. Cell 2007; 129: 1261–1274.
Lin CH, Yeh SH, Lin CH, Lu KT, Leu TH, Chang WC et al. A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 2001; 31: 841–851.
Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Lamothe B et al. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 2009; 325: 1134–1138.
Li R, Wei J, Jiang C, Liu D, Deng L, Zhang K et al. Akt SUMOylation regulates cell proliferation and tumorigenesis. Cancer Res 2013; 73: 5742–5753.
Risso G, Pelisch F, Pozzi B, Mammi P, Blaustein M, Colman-Lerner A et al. Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle. Cell Cycle 2013; 12: 3165–3174.
Geiss-Friedlander R, Melchior F . Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 2007; 8: 947–956.
Hay RT . Decoding the SUMO signal. Biochem Soc Trans 2013; 41: 463–473.
Su YF, Yang T, Huang H, Liu LF, Hwang J . Phosphorylation of Ubc9 by Cdk1 enhances SUMOylation activity. PLoS ONE 2012; 7: e34250.
Knipscheer P, Flotho A, Klug H, Olsen JV, van Dijk WJ, Fish A et al. Ubc9 sumoylation regulates SUMO target discrimination. Mol Cell 2008; 31: 371–382.
Klug H, Xaver M, Chaugule VK, Koid S, Mittler G, Klein F et al. Ubc9 Sumoylation controls SUMO chain formation and meiotic synapsis in Saccharomyces cerevisiae. Mol Cell 2013; 50: 625–636.
Huang J, Yan J, Zhang J, Zhu SG, Wang YL, Shi T et al. SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane. Nat Commun 2012; 3: 911–922.
Fatrai S, Elghazi L, Balcazar N, Cras-Meneur C, Krits I, Kiyokawa H et al. Akt induces β-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity. Diabetes 2006; 55: 318–325.
Yang WL, Wu CY, Wu J, Lin HK . Regulation of Akt signaling activation by ubiquitination. Cell Cycle 2010; 9: 487–497.
de la Cruz-Herrera CF, Campagna M, Lang V, Gonzalez-Santamaria JC, Marcos-Villar L, Rodriguez MS et al. SUMOylation regulates AKT1 activity. Oncogene 2014. 1–9.
Ruggero D, Sonenberg N . The Akt of translational control. Oncogene 2005; 24: 7426–7434.
Facchinetti V, Ouyang W, Wei H, Soto N, Lazorchak A, Gould C et al. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 2008; 27: 1932–1943.
Tai DJC, Su JC, Ma YL, Lee EHY . SGK1 phosphorylation of IKKα and p300 upregulates NF-κB activity and increases NMDA receptor NR2A and NR2B expression. J Biol Chem 2009; 284: 4073–4089.
Acknowledgements
This work was supported by a Grant from the Ministry of Science and Technology in Taiwan (MOST 102-2321-B-001-004). Thank is given to the Proteomics Core Facility of the Institute of Biomedical Sciences, Academia Sinica, Taiwan.
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Lin, C., Liu, S. & Lee, E. SUMO modification of Akt regulates global SUMOylation and substrate SUMOylation specificity through Akt phosphorylation of Ubc9 and SUMO1. Oncogene 35, 595–607 (2016). https://doi.org/10.1038/onc.2015.115
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DOI: https://doi.org/10.1038/onc.2015.115
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