PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY EVENT IN T‐CELL SIGNALING
Interaction between the TCR and MHC–peptide complex is greatly enhanced by recruitment of either co‐receptor for MHC (CD4 or CD8) into the complex. Furthermore, because the cytoplasmic tails of CD4 and CD8 are constitutively associated with Lck, a protein tyrosine kinase (PTK) that can phosphorylate the three tandemly arranged ITAMs within the TCR ζ chains, recruitment of CD4 or CD8 to the complex results in stable association between Lck and its ζ‐chain substrate (Figure 7.8a).
Figure 7.8 Signaling events downstream of T‐cell receptor (TCR) engagement. (a) Engagement of the TCR with the correct peptide–MHC combination leads to CD4/ CD8 recruitment to the TCR complex through interactions with MHC on the antigen‐presenting cell (APC) (note that, for simplicity, co‐stimulation between B7 and CD28 is not depicted). Because CD4 and CD8 are constitutively associated with the Lck kinase, this brings Lck into close proximity to the ITAMs within the CD3 co‐receptor complex. Lck then phosphorylates CD3ζ on multiple sites, that creates binding sites for recruitment of the ZAP‐70 kinase. (b) ZAP‐70 recruitment to the CD3 co‐receptor complex leads to its phosphorylation and activation by Lck. Active ZAP‐70 then propagates TCR signals through phosphorylation of LAT at several sites. Phosphorylated LAT serves as a platform for recruitment of multiple signaling complexes, as depicted. (c) Molecules recruited to LAT instigate three main signaling cascades, as depicted, which cooperatively achieve T‐cell activation. See main text for further details.
Phosphorylation of ζ chain by Lck creates binding sites for the recruitment of another PTK, ZAP‐70 (zeta chain‐ associated protein of 70 kDa), into the TCR signaling complex (Figure 7.9). Recruitment of ZAP‐70 into the receptor complex results in activation of this PTK by Lck‐mediated phosphorylation. ZAP‐70, in turn, phosphorylates two key adaptor proteins, LAT (linker for activation of T‐cells) and SLP‐76 (SH2‐domain containing leukocyte protein of 76 kDa) that can instigate divergent signaling cascades downstream (Figure 7.8b).
Figure 7.9 Interaction between T‐cell and DC. Upon interaction with a DC, T‐cell signaling occurs by the recruitment of ZAP‐70 (green) to the interface between the two cells.
LAT plays an especially significant role in subsequent events by serving as a platform for the recruitment of several additional players to the TCR complex. LAT contains many tyrosine residues that, upon phosphorylation by ZAP‐70, can bind to other adaptor proteins through motifs (called SH2 domains) that bind phosphotyrosine residues. Thus, phospho rylation of LAT results in recruitment of GADS (GRB2‐ related adaptor protein) that is constitutively associated with SLP‐76. SLP‐76 has been implicated in cytoskeletal rearrangements owing to its ability to associate with Vav1 and NCK. Thus, TCR stimulation‐induced cell shape changes are most likely because of recruitment of SLP‐76 into the TCR signaling complex.
Phosphorylated LAT also attracts the attentions of two additional phosphotyrosine‐binding proteins; the γ1 isoform of phospholipase C (PLCγ1), and the adaptor protein GRB2 (growth factor receptor‐binding protein 2). From this point on, at least two distinct signaling cascades can ensue: the Ras–MAP kinase pathway and the phosphatidylinositol pathway (Figure 7.8c).