Vav1 Regulates T-Cell Activation through a Feedback Mechanism and Crosstalk between the T-Cell Receptor and CD28

J Proteome Res. 2015 Jul 2;14(7):2963-75. doi: 10.1021/acs.jproteome.5b00340. Epub 2015 Jun 16.


Vav1, a Rac/Rho guanine nucleotide exchange factor and a critical component of the T-cell receptor (TCR) signaling cascade is tyrosine phosphorylated rapidly in response to T-cell activation. Vav1 has established roles in proliferation, cytokine secretion, Ca(2+) responses, and actin cytoskeleton regulation; however, its function in the regulation of phosphorylation of TCR components, including the ζ chain, the CD3 δ, ε, γ chains, and the associated kinases Lck and ZAP-70, is not well established. To obtain a more comprehensive picture of the role of Vav1 in receptor proximal signaling, we performed a wide-scale characterization of Vav1-dependent tyrosine phosphorylation events using quantitative phosphoproteomic analysis of Vav1-deficient T cells across a time course of TCR stimulation. Importantly, this study revealed a new function for Vav1 in the negative feedback regulation of the phosphorylation of immunoreceptor tyrosine-based activation motifs within the ζ chains, CD3 δ, ε, γ chains, as well as activation sites on the critical T cell tyrosine kinases Itk, Lck, and ZAP-70. Our study also uncovered a previously unappreciated role for Vav1 in crosstalk between the CD28 and TCR signaling pathways.

Keywords: T cell receptor signaling; Vav1; mass spectrometry; phosphoproteomics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CD28 Antigens / metabolism*
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-vav / metabolism
  • Proto-Oncogene Proteins c-vav / physiology*
  • Receptor Cross-Talk*
  • Receptors, Antigen, T-Cell / physiology*
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • ZAP-70 Protein-Tyrosine Kinase / metabolism


  • CD28 Antigens
  • Proto-Oncogene Proteins c-vav
  • Receptors, Antigen, T-Cell
  • VAV1 protein, human
  • Phosphatidylinositol 3-Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human