title: Vav1 oncogenic mutation inhibits T cell receptor-induced calcium mobilization through inhibition of phospholipase Cγ1 activation.
abstract: Robust elevation of the cytosolic calcium concentration is a crucial early step for T cell activation triggered by the T cell antigen receptor. Vav1 is a proto-oncogene expressed in hematopoietic cells that is indispensable for transducing the calcium-mobilizing signal. Following T cell receptor stimulation, Vav1 facilitates formation of signaling microclusters through multiple interactions with other proteins participating in the signaling cascade. Truncation of the N terminus of Vav1 produces its oncogenic version, which is unable to support normal calcium flux following T cell activation. We show here that truncation of the N-terminal region of Vav1 alters the fine structure of protein complexes in the signaling clusters, affecting the interaction of Vav1 with phospholipase Cγ1 (PLCγ1). This alteration is accompanied by a decrease in PLCγ1 phosphorylation and inhibition of inositol 1,4,5-trisphosphate production. We suggest that the structural integrity of the N-terminal region of Vav1 is important for the proper formation of the Vav1-associated signaling complexes. The oncogenic truncation of this region elicits conformational changes that interfere with the Vav1-mediated activation of PLCγ1 and that inhibit calcium mobilization.
authors.affiliation: Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Mira
authors.initials: M
authors.lastname: Knyazhitsky
authors.forename: Etay
authors.initials: E
authors.lastname: Moas
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Shaginov
authors.forename: Anna
authors.initials: A
authors.lastname: Luria
authors.forename: Alex
authors.initials: A
authors.lastname: Braiman
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D009154:Mutation; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496618:VAV1 protein, human; D015544:Inositol 1,4,5-Trisphosphate; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma; D002118:Calcium