Oncotarget

Research Papers:

Mutation of Vav1 adaptor region reveals a new oncogenic activation

Lyra Razanadrakoto, Françoise Cormier, Vanessa Laurienté, Elisabetta Dondi, Laura Gardano, Shulamit Katzav, Lionel Guittat and Nadine Varin-Blank _

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Oncotarget. 2015; 6:2524-2538. https://doi.org/10.18632/oncotarget.2629

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Abstract

Lyra Razanadrakoto1,2,*, Françoise Cormier3,4,5,*, Vanessa Laurienté1,2, Elisabetta Dondi1,2, Laura Gardano1,2, Shulamit Katzav6, Lionel Guittat1,2 and Nadine Varin-Blank1,2

1 INSERM, UMR 978, Bobigny, France

2 PRES SPC, Labex Inflamex, Université Paris 13, UFR SMBH, Bobigny, France

3 INSERM, UMR 1016, Institut Cochin, Paris, France

4 CNRS, UMR 8104, Paris, France

5 PRES SPC, Université Paris Descartes, Paris, France

6 The Hebrew University/ Hadassah Medical School, Jerusalem, Israel

* These authors share co-first authorship

Correspondence:

Nadine Varin-Blank, email:

Lionel Guittat, email:

Keywords: Vav1, β-catenin, Rac GTPase, Src-homology domains, adhesion complex, tumorigenesis

Received: May 14, 2014 Accepted: October 23, 2014 Published: February 10, 2015

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.


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