1 research outputs found
A PLC-γ1 Feedback Pathway Regulates Lck Substrate Phosphorylation at the T‑Cell Receptor and SLP-76 Complex
Phospholipase
C gamma 1 (PLC-γ1) occupies a critically important
position in the T-cell signaling pathway. While its functions as a
regulator of both Ca<sup>2+</sup> signaling and PKC-family kinases
are well characterized, PLC-γ1’s role in the regulation
of early T-cell receptor signaling events is incompletely understood.
Activation of the T-cell receptor leads to the formation of a signalosome
complex between SLP-76, LAT, PLC-γ1, Itk, and Vav1. Recent studies
have revealed the existence of both positive and negative feedback
pathways from SLP-76 to the apical kinase in the pathway, Lck. To
determine if PLC-γ1 contributes to the regulation of these feedback
networks, we performed a quantitative phosphoproteomic analysis of
PLC-γ1-deficient T cells. These data revealed a previously unappreciated
role for PLC-γ1 in the positive regulation of Zap-70 and T-cell
receptor tyrosine phosphorylation. Conversely, PLC-γ1 negatively
regulated the phosphorylation of SLP-76-associated proteins, including
previously established Lck substrate phosphorylation sites within
this complex. While the positive and negative regulatory phosphorylation
sites on Lck were largely unchanged, Tyr<sup>192</sup> phosphorylation
was elevated in Jgamma1. The data supports a model wherein Lck’s
targeting, but not its kinase activity, is altered by PLC-γ1,
possibly through Lck Tyr<sup>192</sup> phosphorylation and increased
association of the kinase with protein scaffolds SLP-76 and TSAd