PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY EVENT IN T‐CELL SIGNALING - pediagenosis
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Wednesday, October 21, 2020

PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY EVENT IN T‐CELL SIGNALING

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 coreceptor 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 ζchain substrate (Figure 7.8a).

Figure 7.8 Signaling events downstream of Tcell 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 antigenpresenting cell (APC) (note that, for simplicity, costimulation 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 coreceptor complex. Lck then phosphorylates CD3ζ on multiple sites, that creates binding sites for recruitment of the ZAP70 kinase. (b) ZAP70 recruitment to the CD3 coreceptor complex leads to its phosphorylation and activation by Lck. Active ZAP70 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 Tcell activation. See main text for further details.

Phosphorylation of ζ chain by Lck creates binding sites for the recruitment of another PTK, ZAP70 (zeta chain associated protein of 70 kDa), into the TCR signaling complex (Figure 7.9). Recruitment of ZAP70 into the receptor complex results in activation of this PTK by Lckmediated phosphorylation. ZAP70, in turn, phosphorylates two key adaptor proteins, LAT (linker for activation of Tcells) and SLP76 (SH2domain containing leukocyte protein of 76 kDa) that can instigate divergent signaling cascades downstream (Figure 7.8b).

Figure 7.9 Interaction between Tcell and DC. Upon interaction with a DC, Tcell signaling occurs by the recruitment of ZAP70 (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 ZAP70, 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 SLP76. SLP76 has been implicated in cytoskeletal rearrangements owing to its ability to associate with Vav1 and NCK. Thus, TCR stimulationinduced cell shape changes are most likely because of recruitment of SLP76 into the TCR signaling complex.

Phosphorylated LAT also attracts the attentions of two additional phosphotyrosinebinding proteins; the γ1 isoform of phospholipase C (PLCγ1), and the adaptor protein GRB2 (growth factor receptorbinding 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).


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