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Mutation of Vav1 adaptor region reveals a new oncogenic activation

Abstract : Vav family members function as remarkable scaffold proteins that exhibit both GDP/GTP exchange activity for Rho/Rac GTPases and numerous protein-protein interactions via three adaptor Src-homology domains. The exchange activity is under the unique regulation by phosphorylation of tyrosine residues hidden by intra-molecular interactions. Deletion of the autoinhibitory N-terminal region results in an oncogenic protein, onco-Vav, leading to a potent activation of Rac GTPases whereas the proto-oncogene barely leads to transformation. Substitution of conserved residues of the SH2-SH3 adaptor region in onco-Vav reverses oncogenicity. While a unique substitution D797N did not affect transformation induced by onco-Vav, we demonstrate that this single substitution leads to transformation in the Vav1 proto-oncogene highlighting the pivotal role of the adaptor region. Moreover, we identified the cell junction protein β-catenin as a new Vav1 interacting partner. We show that the oncogenicity of activated Vav1 proto-oncogene is associated with a non-degradative phosphorylation of β-catenin at residues important for its functions and its redistribution along the cell membrane in fibroblasts. In addition, a similar interaction is evidenced in epithelial lung cancer cells expressing ectopically Vav1. In these cells, Vav1 is also involved in the modulation of β-catenin phosphorylation. Altogether, our data highlight that only a single mutation in the proto-oncogene Vav1 enhances tumorigenicity. INTRODUCTION The Vav1 proto-oncogene has a restricted hematopoietic expression and exhibits both GTP/GDP exchange activities (GEF) for Rho family GTPases and adaptor functions within signalling complexes [1, 2]. Two other genes, Vav2 and Vav3 belong to the same family of signalling effectors and share high structural similarities and properties with Vav1. Unlike Vav1, Vav2 and Vav3 have an ubiquitous expression [3, 4]. Vav proteins display a number of characteristic structural domains with homology for: Calponin (CH), Dbl (DH), Pleckstrin (PH) and Src (SH2 and SH3) altogether with acidic residues-rich (AcR) and cysteine-rich (CR) motives. These domains mediate interactions with membrane receptors,
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Submitted on : Monday, August 3, 2015 - 2:49:00 PM
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  • HAL Id : inserm-01182781, version 1
  • PUBMED : 25426554

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Lyra Razanadrakoto, Françoise Cormier, Vanessa Laurienté, Elisabetta Dondi, Laura Gardano, et al.. Mutation of Vav1 adaptor region reveals a new oncogenic activation. Oncotarget, Impact journals, 2015, pp.2524-37. ⟨inserm-01182781⟩

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