title: 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.
authors.affiliation: INSERM, UMR 978, Bobigny, France.|PRES SPC, Labex Inflamex, Université Paris 13, UFR SMBH, Bobigny, France.
authors.forename: Lyra
authors.initials: L
authors.lastname: Razanadrakoto
authors.affiliation: INSERM, UMR 1016, Institut Cochin, Paris, France.|CNRS, UMR 8104, Paris, France.|PRES SPC, Université Paris Descartes, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Cormier
authors.affiliation: INSERM, UMR 978, Bobigny, France.|PRES SPC, Labex Inflamex, Université Paris 13, UFR SMBH, Bobigny, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Laurienté
authors.affiliation: INSERM, UMR 978, Bobigny, France.|PRES SPC, Labex Inflamex, Université Paris 13, UFR SMBH, Bobigny, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dondi
authors.affiliation: INSERM, UMR 978, Bobigny, France.|PRES SPC, Labex Inflamex, Université Paris 13, UFR SMBH, Bobigny, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Gardano
authors.affiliation: The Hebrew University/ Hadassah Medical School, Jerusalem, Israel.
authors.forename: Shulamit
authors.initials: S
authors.lastname: Katzav
authors.affiliation: INSERM, UMR 978, Bobigny, France.|PRES SPC, Labex Inflamex, Université Paris 13, UFR SMBH, Bobigny, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Guittat
authors.affiliation: INSERM, UMR 978, Bobigny, France.|PRES SPC, Labex Inflamex, Université Paris 13, UFR SMBH, Bobigny, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Varin-Blank
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics*
chemical_list: D000873:Anthracenes; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D051176:beta Catenin; C432165:pyrazolanthrone; D001224:Aspartic Acid; D048670:MAP Kinase Kinase 4