Akt SUMOylation Regulates Cell Proliferation and Tumorigenesis

Abstract

Proto-oncogene Akt plays essential roles in cell proliferation and tumorigenesis. Full activation of Akt is regulated by phosphorylation, ubiquitination, and acetylation. Here we report that SUMOylation of Akt is a novel mechanism for its activation. Systematically analyzing the role of lysine residues in Akt activation revealed that K276, which is located in a SUMOylation consensus motif, is essential for Akt activation. Ectopic or endogenous Akt1 could be modified by SUMOylation. RNA interference-mediated silencing of UBC9 reduced Akt SUMOylation, which was promoted by SUMO E3 ligase PIAS1 and reversed by the SUMO-specific protease SENP1. Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity. Interestingly, the cancerderived mutant E17K in Akt1 that occurs in various cancers was more efficiently SUMOylated than wild-type Akt. Moreover, SUMOylation loss dramatically reduced Akt1 E17K-mediated cell proliferation, cell migration, and tumorigenesis. Collectively, our findings establish that Akt SUMOylation provides a novel regulatory mechanism for activating Akt function. Cancer Res; 73(18); 5742-53. Ó2013 AACR.

Phenotypic and Signaling Consequences of a Novel Aberrantly Spliced Transcript FGF Receptor-3 in Hepatocellular Carcinoma

“…All identified mutations occur at highly conserved sequences, not only in the molecules of FGFR family but also throughout evolution and are clustered in the Ig-like loop-III domain, highlighting the functional importance of this domain. All the observations support that FGFR3 represents an important example of single-gene, causing different human developmental and tumor diseases (37).…”

“…The ligand-binding site of FGFRs was localized to Ig-like-II and -III domains (22,27,37). In this study, FGFR3 D7-9 mutant can stably satisfy FGF1 or FGF2 binding requests, and showed a much more strong affinity to FGFs than wild-type FGFR3.…”

Protein Inhibitor of Activated STAT 1 (PIAS1) Protects Against Obesity-Induced Insulin Resistance by Inhibiting Inflammation Cascade in Adipose Tissue

“…For example, the oncogene AKT, a mediator of growth-factor signaling, is essential in cell proliferation and tumorigenesis (41). The SUMOylation of AKT, which has recently been reported, is required for its kinase activity and is essential for cell growth and tumorigenesis as well (42). It is possible that PIAS1 could directly induce SUMOylation of the proteins in the insulin-signaling pathway, such as IR or IRS, thereby modulating insulin sensitivity.…”

Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle

“…Furthermore, they found that this PTM influences Akt activity at cell proliferation and tumor development and, consistent with our findings, showed that diminishing SUMO conjugation to the cancer-associated mutant Akt1 E17K reduces its oncogenic capacity. 52 Our results together with these findings reveal twenty-four h after transfection cells were treated with the pi3K inhibitor LY 294002 (LY) for another 24 h before cell lysis. An aliquot of the lysates was taken as input and the reminder was subject to denaturing Ni 2+ affinity chromatography.…”