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

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, Ca2+ 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.