Sequential Interactions of the TCR with Two Distinct Cytoplasmic Tyrosine Kinases

TLDR

The T cell antigen receptor initiates signaling by engaging cytoplasmic protein tyrosine kinases through a 17‑residue ARAM motif in its ζ and CD3 chains, initiating a sequential PTK interaction cascade. Upon TCR engagement, Lck phosphorylates two conserved tyrosines in the ARAM, enabling ZAP‑70 recruitment through its SH2 domains and subsequent phosphorylation.

Abstract

The T cell antigen receptor (TCR) initiates signals by interacting with cytoplasmic protein tyrosine kinases (PTKs) through a 17-residue sequence motif [called the antigen recognition activation motif (ARAM)] that is contained in the TCRζ and CD3 chains. TCR stimulation induces the tyrosine phosphorylation of several cellular substrates, including the ARAMs. Lck kinase activity is required for phosphorylation of two conserved tyrosine residues in an ARAM. This phosphorylation leads to the recruitment of a second cytoplasmic PTK, ZAP-70, through both of the ZAP-70 Src homology 2 domains and its phosphorylation. Thus, TCR signal transduction is initiated by the sequential interaction of two PTKs with TCR ARAMs.