title: Vav1 acidic region tyrosine 174 is required for the formation of T cell receptor-induced microclusters and is essential in T cell development and activation.
abstract: Vav proteins are multidomain signaling molecules critical for mediating signals downstream of several surface receptors, including the antigen receptors of T and B lymphocytes. The catalytic guanine nucleotide exchange factor (GEF) activity of the Vav Dbl homology (DH) domain is thought to be controlled by an intramolecular autoinhibitory mechanism involving an N-terminal extension and phosphorylation of tyrosine residues in the acidic region (AC). Here, we report that the sequences surrounding the Vav1 AC: Tyr(142), Tyr(160), and Tyr(174) are evolutionarily conserved, conform to consensus SH2 domain binding motifs, and bind several proteins implicated in TCR signaling, including Lck, PI3K p85alpha, and PLCgamma1, through direct interactions with their SH2 domains. In addition, the AC tyrosines regulate tyrosine phosphorylation of Vav1. We also show that Tyr(174) is required for the maintenance of TCR-signaling microclusters and for normal T cell development and activation. In this regard, our data demonstrate that while Vav1 Tyr(174) is essential for maintaining the inhibitory constraint of the DH domain in both developing and mature T cells, constitutively activated Vav GEF disrupts TCR-signaling microclusters and leads to defective T cell development and proliferation.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Ana V
authors.initials: AV
authors.lastname: Miletic
authors.forename: Kumiko
authors.initials: K
authors.lastname: Sakata-Sogawa
authors.forename: Michio
authors.initials: M
authors.lastname: Hiroshima
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hamann
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Gomez
authors.forename: Naruhisa
authors.initials: N
authors.lastname: Ota
authors.forename: Tracie
authors.initials: T
authors.lastname: Kloeppel
authors.forename: Osami
authors.initials: O
authors.lastname: Kanagawa
authors.forename: Makio
authors.initials: M
authors.lastname: Tokunaga
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
mesh_terms: D049109:Cell Proliferation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D010766:Phosphorylation; D051567:Proto-Oncogene Proteins c-vav / Q000737:chemistry / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology*; D014443:Tyrosine / Q000502:physiology*; D018909:src Homology Domains
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496618:VAV1 protein, human; D014443:Tyrosine