Vav1 regulates T cell activation through a feedback mechanism and crosstalk between the T cell receptor and CD28 in CD3-stimulated T cells

ABSTRACT: Vav1, a Rac/Rho guanine nucleotide exchange factor and a critical component of the T cell receptor (TCR) signaling cascade, is rapidly tyrosine phosphorylated in response to T cell activation. Previous studies using Vav1 knockout models have demonstrated its importance in TCR signaling. Although Vav1 has established roles in proliferation, cytokine secretion, Ca2+ responses, and cytoskeletal regulation, 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. Among the 642 tyrosine phosphorylation sites identified and quantified in cells with or without Vav1, we observed statistically significant alterations in phosphorylation on proteins implicated in canonical actin cytoskeletal rearrangement and cell cycle progression, supporting the previously established role of Vav1 in these functions of TCR signaling. Critically, this study revealed a new role for Vav1 in 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.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Arthur Salomon  

LAB HEAD: Arthur Salomon

PROVIDER: PXD002022 | Pride | 2016-05-31

REPOSITORIES: Pride