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SUMOylation modulates the stability and function of PI3K-p110β

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Abstract

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.

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Availability of data and materials

All data generated or analysed during this study are included in this published article. The materials used in this study are available from the corresponding authors, CR, upon reasonable request.

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Abbreviations

CHX:

Cycloheximide

PI3Ks:

Phosphatidylinositol-4,5,bisphosphate 3-kinases

SUMO:

Small ubiquitin-related modifier

SENP1:

SUMO specific protease 1

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Acknowledgements

We thank Dr, Jonathan M Backer for kindly providing the myc-p110β plasmid and Dr. Lewis Cantley for the HA-tagged p110α expression plasmid. Funding at the laboratory of CR is provided by Ministry of Science, Innovation and Universities and FEDER (BFU-2017–88,880-P) and Xunta de Galicia (ED431G 2019/02). SV and RS are predoctoral fellows funded by Xunta de Galicia-Consellería de Cultura, Educación y Ordenación Universitaria (ED481A-2018/110 and ED481A-2020/160, respectively).

Funding

Funding at the laboratory of CR is provided by Ministry of Science, Innovation and Universities and FEDER (BFU-2017-88880-P) and Xunta de Galicia (ED431G 2019/02). The laboratory of MC is funded by grant RTI2018-095818-B-100 (MCIU/AEI/ FEDER, UE). SV and RS are predoctoral fellows funded by Xunta de Galicia-Consellería de Cultura, Educación y Ordenación Universitaria (ED481A-2018/110 and ED481A-2020/160, respectively).

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Author notes

  1. Ahmed El Motiam and Carlos F de la Cruz-Herrera, equal contribution.

Authors and Affiliations

  1. 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

    Ahmed El Motiam, Santiago Vidal, Rocío Seoane, Maite Baz-Martínez, Yanis H. Bouzaher, Anxo Vidal & Carmen Rivas

  2. Department of Molecular Genetics, University of Toronto, 1 Kings College Circle, Toronto, M5S 1A8, Canada

    Carlos F. de la Cruz-Herrera

  3. Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain

    Emilio Lecona

  4. Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CNB), CSIC, Darwin 3, 28049, Madrid, Spain

    Mariano Esteban & Carmen Rivas

  5. Laboratoire de Chimie de Coordination LCC-UPR 8241-CNRS, Toulouse, France

    Manuel S. Rodríguez

  6. IPBS-University of Toulouse III-Paul Sabatier, Toulouse, France

    Manuel S. Rodríguez

  7. Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, 15706, Santiago de Compostela, Spain

    Manuel Collado

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  1. Ahmed El Motiam
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Contributions

AEM, CFC-H, SV, RS, YHB, and MB-M conducted the experiments; ME and MSR generated reagents; AV, MSR, ME, MC, EL, and CR analyzed the results; CR, designed the experiments and wrote the paper.

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Correspondence to Carmen Rivas.

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El Motiam, A., de la Cruz-Herrera, C.F., Vidal, S. et al. SUMOylation modulates the stability and function of PI3K-p110β. Cell. Mol. Life Sci. 78, 4053–4065 (2021). https://doi.org/10.1007/s00018-021-03826-6

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