Early phosphorylation kinetics of proteins involved in proximal TCR-mediated signaling pathways

Jon C.D. Houtman, Richard A. Houghtling, Mira Barda-Saad, Yoko Toda, Lawrence E. Samelson

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Activation of T cells via the stimulation of the TCR plays a central role in the adaptive immunological response. Although much is known about TCR-stimulated signaling pathways, there are still gaps in our knowledge about the kinetics and sequence of events during early activation and about the in vivo specificity of kinases involved in these proximal signaling pathways. This information is important not only for understanding the activation of signaling pathways important for T cell function but also for the development of drug targets and computer-based molecular models. In this study, phospho-specific Abs directed toward individual sites on signaling proteins were used to investigate the early phosphorylation kinetics of proteins involved in proximal TCR-induced pathways. These studies indicate that linker for activation of T cells' tyrosines have substantially different phosphorylation kinetics and that Src homology 2 domain-containing leukocyte protein of 76 kDa has rapid, transient phosphorylation kinetics compared to other proteins. In additions, we provide evidence that ZAP-70 is the primary in vivo kinase for LAT tyrosine 191 and that Itk plays a role in the phosphorylation of tyrosine 783 on phospholipase C-γ1. In total, these studies give new insight into the sequence, kinetics and specificity of early TCR-mediated signaling events that are vital for T cell activation.

Original languageEnglish
Pages (from-to)2449-2458
Number of pages10
JournalJournal of Immunology
Volume175
Issue number4
DOIs
StatePublished - 15 Aug 2005
Externally publishedYes

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