title: The N-terminal 20-amino acid region of guanine nucleotide exchange factor Vav1 plays a distinguished role in T cell receptor-mediated calcium signaling.
abstract: Vav1 is a guanine nucleotide exchange factor (GEF) specifically expressed in hematopoietic cells. It consists of multiple structural domains and plays important roles in T cell activation. The other highly conserved isoforms of Vav family, Vav2 and Vav3, are ubiquitously expressed in human tissues including lymphocytes. All three Vav proteins activate Rho family small GTPases, which are involved in a variety of biological processes during T cell activation. Intensive studies have demonstrated that Vav1 is indispensable for T cell receptor (TCR)-mediated signal transduction, whereas Vav2 and Vav3 function as GEFs that overlap with Vav1 on TCR-induced cytoskeleton reorganization. T cells lacking Vav1 exhibited severe defect in TCR-mediated calcium elevation, indicating that the co-existing Vav2 and Vav3 did not compensate Vav1 in calcium signaling. What is the functional particularity of Vav1 in lymphocytes? In this study, we identified the N-terminal 20 amino acids of Vav1 in the calponin homology (CH) domain to be essential for its interaction with calmodulin (CaM) that leads to TCR-induced calcium mobilization. Substitution of the 1-20 amino acids of Vav1 with those of Vav2 or Vav3 abolished the association with CaM, and the N-terminal mutations of Vav1 failed to potentiate normal TCR-induced calcium mobilization, that in turn, suspended nuclear factor of activated T cells (NFAT) activation and IL-2 production. This study highlights the importance of the N-terminal 20 aa of Vav1 for CaM binding, and provides new insights into the distinguished and irreplaceable role of Vav1 in T cell activation and signal transduction.
authors.affiliation: Key Laboratory of Microbial Functional Genomics of the Ministry of Education, Medicinal Chemical Biology College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, Peoples Republic of China.
authors.forename: Shi-Yang
authors.initials: SY
authors.lastname: Li
authors.forename: Ming-Juan
authors.initials: MJ
authors.lastname: Du
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Wan
authors.forename: Bei
authors.initials: B
authors.lastname: Lan
authors.forename: Yao-Hui
authors.initials: YH
authors.lastname: Liu
authors.forename: Yin
authors.initials: Y
authors.lastname: Yang
authors.forename: Cui-Zhu
authors.initials: CZ
authors.lastname: Zhang
authors.forename: Youjia
authors.initials: Y
authors.lastname: Cao
mesh_terms: D020013:Calcium Signaling / Q000502:physiology*; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000502:physiology*; D009154:Mutation; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*
chemical_list: D002147:Calmodulin; C508594:IL2 protein, human; D007376:Interleukin-2; D020033:Protein Isoforms; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496618:VAV1 protein, human