Expert Reviews in Molecular Medicine: http://www.expertreviews.org/
Accession information: Vol. 7; Issue 29; 20 December 2005 Abstract
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Adaptors and molecular scaffolds in T-cell signalling

Beverley Wilkinson, Jocelyn S. Downey and Christopher E. Rudd

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Figure 3. Adaptors and molecular scaffolds in T-cell signalling. Ligation of the T-cell receptor results in activation of the Syk-family protein tyrosine kinase ZAP-70 (see Fig. 2). ZAP-70 subsequently phosphorylates LAT (localised to a lipid raft) and SLP-76, allowing them to interact with SH2-containing proteins. SLP-76 and its associated molecules are recruited to LAT in the plasma membrane through an interaction with GADS. This leads to the SLP-76-dependent activation of PLCg1, dependent on kinases ITK and RLK, which results in protein kinase C activation (not shown), intracellular Ca²⁺ mobilisation, and NFAT-mediated transcription. Phosphorylation of SLP-76 allows SH2-mediated binding to the adaptors VAV and NCK. The NCK–VAV–SLP-76 complex binds to WASP, which activates the Arp2/3 complex, leading to cytoskeletal reorganisation. SLP-76 also binds to ADAP in a pathway that is modulated by Fyn. ADAP in turn associates with SKAP-55, which is also needed for integrin clustering and adhesion. In addition, ADAP binds to Ena/VASP proteins, which, together with Cdc42 and WASP, influences actin remodelling. The putative SLP-76–ADAP–SKAP-55 complex is required for integrin (i.e. LFA-1) clustering and adhesion, and SMAC formation at the immunological synapse. The GTP-binding protein Rap-1 and its ligand RapL act further downstream in this pathway. In the figure, red arrows indicate the action of kinases; blue arrows indicate associations with adaptor proteins; and green arrows indicate downstream effector functions. Abbreviations: ADAP, adhesion-and degranulation-promoting protein; Arp2/3, actin-related proteins 2 and 3; GADS, Grb2-related adaptor downstream of Shc; ITK, IL-2-inducible kinase; LAT, linker for activation of T cells; LFA-1, leukocyte function-associated antigen 1; NCK, noncatalytic region of tyrosine kinase adaptor protein 1; NFAT, nuclear factor for the activation of T cells; PLCg1, phospholipase Cg1; RLK, resting T-cell kinase; SKAP-55, Src-family-kinase-associated phosphoprotein of 55 kDa; SH2, Src-homology 2; SLP-76, SH2-domain-containing leukocyte protein of 76 kDa; SMAC, supramolecular complex; VASP, vasodilator-stimulated phosphoprotein; WASP, Wiskott Aldrich syndrome protein; ZAP-70, zeta-associated protein 70.

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