Conjugation of SUMO to p85 leads to a novel mechanism of PI3K regulation

Abstract

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.

DOI: 10.1038/onc.2015.356

Cite this paper

@article{CruzHerrera2016ConjugationOS, title={Conjugation of SUMO to p85 leads to a novel mechanism of PI3K regulation}, author={C F de la Cruz-Herrera and Maite Baz-Mart{\'i}nez and Verena Lang and Ahmed El Motiam and Jorge Barbaz{\'a}n and Rita Couceiro and Miguel Abal and Anabel Vidal and Mariano Est{\'e}ban and Cesar Munoz-Fontela and Antonio Nieto and Manuel Santa-Cruz Rodr{\'i}guez and Mar{\'i}a del Carmen Collado and Concepci{\'o}n Rivas}, journal={Oncogene}, year={2016}, volume={35}, pages={2873-2880} }