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

Oncogene volume 35, pages 2873–2880 (2016)Cite this article

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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.

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Acknowledgements

We thank Drs Lewis Cantley and Lynda Chin who deposited p85 plasmids at Addgene. Funding at the laboratory of CR is provided by BFU2014-58530. CFC-H is supported by La Caixa fellowship and CONACYT. Work in the laboratory of MC is funded by ISCIII (PI14/00554). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Departmento de Biología Molecular y Celular, Centro Nacional de Biotecnología-CSIC, Darwin 3, Madrid, Spain

    C F de la Cruz-Herrera, M Esteban, A Nieto & C Rivas

  2. Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain

    M Baz-Martínez, A El Motiam, A Vidal & C Rivas

  3. Ubiquitylation and Cancer Molecular Biology Laboratory, Inbiomed, San Sebastian-Donostia, Gipuzkoa, Spain

    V Lang & M S Rodríguez

  4. Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS),

    J Barbazán, R Couceiro, M Abal & M Collado

  5. , SERGAS, Santiago de Compostela, Spain

    J Barbazán, R Couceiro, M Abal & M Collado

  6. Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany

    C Muñoz-Fontela

  7. CIBER de Enfermedades Respiratorias (CIBERES), Illes Balears, Mallorca, Spain

    A Nieto

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  1. C F de la Cruz-Herrera
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Correspondence to C Rivas.

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de la Cruz-Herrera, C., Baz-Martínez, M., Lang, V. et al. Conjugation of SUMO to p85 leads to a novel mechanism of PI3K regulation. Oncogene 35, 2873–2880 (2016). https://doi.org/10.1038/onc.2015.356

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