Centro de Investigación en Medicina Molecular (CIMUS), CIMUS, P2L7, Universidade de Santiago de Compostela and Instituto de Investigaciones Sanitarias (IDIS), Avda Barcelona, 15706, Santiago de Compostela, Spain.
Department of Molecular Genetics, University of Toronto, 1 Kings College Circle, Toronto, M5S 1A8, Canada.
Cell Mol Life Sci. 2021 Apr;78(8):4053-4065. doi: 10.1007/s00018-021-03826-6. Epub 2021 Apr 8.
Class I PI3K are heterodimers composed of a p85 regulatory subunit and a p110 catalytic subunit involved in multiple cellular functions. Recently, the catalytic subunit p110β has emerged as a class I PI3K isoform playing a major role in tumorigenesis. Understanding its regulation is crucial for the control of the PI3K pathway in p110β-driven cancers. Here we sought to evaluate the putative regulation of p110β by SUMO. Our data show that p110β can be modified by SUMO1 and SUMO2 in vitro, in transfected cells and under completely endogenous conditions, supporting the physiological relevance of p110β SUMOylation. We identify lysine residue 952, located at the activation loop of p110β, as essential for SUMOylation. SUMOylation of p110β stabilizes the protein increasing its activation of AKT which promotes cell growth and oncogenic transformation. Finally, we show that the regulatory subunit p85β counteracts the conjugation of SUMO to p110β. In summary, our data reveal that SUMO is a novel p110β interacting partner with a positive effect on the activation of the PI3K pathway.
I 类 PI3K 是由 p85 调节亚基和 p110 催化亚基组成的异二聚体，参与多种细胞功能。最近，p110β 催化亚基作为 I 类 PI3K 同工型出现，在肿瘤发生中发挥主要作用。了解其调控对于控制 p110β 驱动的癌症中的 PI3K 途径至关重要。在这里，我们试图评估 SUMO 对 p110β 的潜在调节作用。我们的数据表明，p110β 可以在体外、转染细胞中和完全内源性条件下被 SUMO1 和 SUMO2 修饰，支持 p110β SUMO 化的生理相关性。我们确定了位于 p110β 激活环中的赖氨酸残基 952 对于 SUMO 化是必不可少的。p110β 的 SUMO 化稳定了蛋白质，增加了其对 AKT 的激活，促进了细胞生长和致癌转化。最后，我们表明调节亚基 p85β 拮抗 SUMO 与 p110β 的缀合。总之，我们的数据表明 SUMO 是 p110β 的一种新型相互作用伙伴，对 PI3K 途径的激活有积极影响。
