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VAV2 regulates epidermal growth factor receptor endocytosis and degradation

Abstract

Vav proteins are guanine nucleotide exchange factors for Rho GTPases that regulate cell adhesion, motility, spreading and proliferation in response to growth factor signalling. In this work, we show that Vav2 expression delayed epidermal growth factor receptor (EGFR) internalization and degradation, and enhanced EGFR, ERK and Akt phosphorylations. This effect of Vav2 on EGFR degradation is dependent on its guanine nucleotide exchange function. Knockdown of Vav2 in HeLa cells enhanced EGFR degradation and reduced cell proliferation. epidermal growth factor stimulation led to co-localization of Vav2 with EGFR and Rab5 in endosomes. We further show that the effect of Vav2 on EGFR stability is modulated by its interaction with two endosome-associated proteins and require RhoA function. Thus, in this work, we report for the first time that Vav2 can regulate growth factors receptor signalling by slowing receptor internalization and degradation through its interaction with endosome-associated proteins.

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Abbreviations

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

PDGFR:

platelet-derived growth factor receptor

MVB:

multivesicular bodies

ESCRT:

endosomal sorting complex required for transport

GFP:

green fluorescent protein

CXM:

cycloheximide

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Acknowledgements

We gratefully acknowledge M Seux for help throughout the work and P Spotto for technical help. Dr Alan Saltiel (University of Michigan, Ann Arbor, MI, USA) kindly provided Gapvd1 constructs and Dr László Buday (Semmelweis University, Budapest, Hungary) Vav2–GFP plasmids. This work was supported in part by INSERM and grants from the Ligue Contre le Cancer. ST was supported by a postdoctoral fellowship from ARC (Association pour la Recherche sur le Cancer).

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Thalappilly, S., Soubeyran, P., Iovanna, J. et al. VAV2 regulates epidermal growth factor receptor endocytosis and degradation. Oncogene 29, 2528–2539 (2010). https://doi.org/10.1038/onc.2010.1

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Keywords

  • VAV2
  • EGFR
  • endosome
  • receptor internalization

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