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Mutation of Vav1 adaptor region reveals a new oncogenic activation

2014; Impact Journals LLC; Volume: 6; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.2629

1949-2553

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

Hippo pathway signaling and YAP/TAZ

// Lyra Razanadrakoto 1,2,* , Françoise Cormier 3,4,5,* , Vanessa Laurienté 1,2 , Elisabetta Dondi 1,2 , Laura Gardano 1,2 , Shulamit Katzav 6 , Lionel Guittat 1,2 and Nadine Varin-Blank 1,2 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.