相扑蛋白
生物
磷酸化
PI3K/AKT/mTOR通路
细胞生物学
酪氨酸磷酸化
酪氨酸
SH2域
磷脂酰肌醇
信号转导
突变体
生物化学
泛素
基因
作者
Carlos F. de la Cruz-Herrera,Maite Baz-Martínez,V. S. Lang,Ahmed El Motiam,Jorge Barbazán,R Couceiro,Miguel Abal,Anxo Vidal,Mariano Estéban,César Muñoz‐Fontela,Amelia Nieto,Manuel S. Rodríguez,Manuel Collado,Carmen Rivas
出处
期刊:Oncogene
[Springer Nature]
日期:2015-09-28
卷期号:35 (22): 2873-2880
被引量:25
摘要
Class IA phosphatidylinositol 3-kinases (PI3Ks) are composed of p110 catalytic and p85 regulatory subunits. How regulatory subunits modulate PI3K activity remains only partially understood. Here we identified SUMO (small ubiquitin-related modifier) as a new player modulating this regulation. We demonstrate that both p85β and p85α are conjugated to SUMO1 and SUMO2. We identified two lysine residues located at the inter-SH2 domain on p85β, a critical region required for inhibition of p110, as being required for SUMO conjugation. A SUMOylation-defective mutant p85β shows higher activation of the PI3K pathway, and increased cell migration and transformation. Moreover, the cancer-related KS459del mutant in p85α was less efficiently SUMOylated compared with the wild-type protein. Finally, our results show that SUMO modulates p85 tyrosine phosphorylation, a modification correlating with PI3K pathway activation. Thus, SUMO reduces the levels of tyrosine-phosphorylated-p85 while loss of SUMOylation results in increased tyrosine phosphorylation of p85. In summary, we identify SUMO as a new important player in the regulation of the PI3K pathway through modulation of p85.
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