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The ubiquitin-specific protease USP2a prevents endocytosis-mediated EGFR degradation

Oncogene volume 32, pages 1660–1669 (2013)Cite this article

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Abstract

Ubiquitination of epidermal growth factor receptor (EGFR) is required for downregulation of the receptor by endocytosis. Impairment of this pathway results in constitutively active EGFR, which is associated with carcinogenesis, particularly in lung cancer. We previously demonstrated that the deubiquitinating enzyme ubiquitin-specific protease 2a (USP2a) has oncogenic properties. Here, we show a new role for USP2a as a regulator of EGFR endocytosis. USP2a localizes to early endosomes and associates with EGFR, stabilizing the receptor, which retains active downstream signaling. HeLa cells transiently expressing catalytically active, but not mutant (MUT), USP2a show increased plasma membrane-localized EGFR, as well as decreased internalized and ubiquitinated EGFR. Conversely, USP2a silencing reverses this phenotype. Importantly, USP2a prevents the degradation of MUT in addition to wild-type EGFR. Finally, we observed that USP2a and EGFR proteins are coordinately overexpressed in non-small cell lung cancers. Taken together, our data indicate that USP2a antagonizes EGFR endocytosis and thus amplifies signaling activity from the receptor. Our findings suggest that regulation of deubiquitination could be exploited therapeutically in cancers overexpressing EGFR.

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Abbreviations

CHC:

clathrin heavy chain

DUB:

deubiquitinating enzyme

EEA1:

early endosomal antigen

EGFR:

epidermal growth factor receptor

WT:

wild type

MUT:

mutant

RTK:

receptor tyrosine kinase

TfR:

transferrin receptor

USP2:

ubiquitin-specific protease 2

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Acknowledgements

We thank Tomas Kirchhausen for AMSH constructs, Mihee Ji and Erik McCauley for technical assistance, Jane Hayward for help with preparation of the figures, Giulio Draetta and Richard J Flavin for critical reading of the manuscript. This work was supported by the National Cancer Institute (RO1CA131945, PO1CA89021, P50 CA90381 and the Prostate Cancer Foundation). SMZ was supported by CAPES (no. 3665/10-0), Brazil.

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Author notes

  1. Z Liu and S M Zanata: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA

    Z Liu, S M Zanata, M A Peterson, L R Chirieac, S Pyne, M Agostini & M Loda

  2. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

    Z Liu & M Loda

  3. Departments of Basic Pathology and Cell Biology, Universidade Federal do Parana, Curitiba, Brazil

    S M Zanata

  4. The Urological Diseases Research Center, Children’s Hospital Boston, Boston, MA, USA

    J Kim, D Di Vizio & M R Freeman

  5. Department of Surgery, Harvard Medical School, Boston, MA, USA

    J Kim, D Di Vizio & M R Freeman

  6. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    M R Freeman

  7. Division of Cancer Studies, King’s College London, London, UK

    M Loda

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Liu, Z., Zanata, S., Kim, J. et al. The ubiquitin-specific protease USP2a prevents endocytosis-mediated EGFR degradation. Oncogene 32, 1660–1669 (2013). https://doi.org/10.1038/onc.2012.188

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