|
|
|
|
|
|
|
|
|
|
Expert
Reviews in Molecular Medicine: http://www.expertreviews.org/
Accession information: Vol. 7; Issue 29; 20 December 2005 Abstract
PDF
The T-cell signalling paradigm
Beverley Wilkinson, Jocelyn S. Downey and Christopher E. Rudd
Figure 2. The T-cell signalling paradigm. (a) Initial phosphorylation events. Ligation of the TCRz–CD3 complex and CD4/CD8–Lck induces phosphorylation of ITAMs on the TCRz and CD3 chains. Phosphorylated ITAMs then bind in tandem to two SH2 domains of ZAP-70. Tyrosine phosphatase CD45 maintains activation of Lck by dephosphorylation of an inhibitory C-terminal phosphate. Subsequent events include Lck phosphorylation and binding to ZAP-70, resulting in ZAP-70 activation and the regulation of downstream substrates (i.e. adaptors LAT and SLP-76). (b) Regulation of Lck. The phosphorylated C-terminal tyrosine residue Y505 of Lck interacts with the internal SH2 domain, holding it in a closed, inactive state. In resting T cells, Cbp (Csk-binding protein)/PAG (phosphoprotein associated with glycosphingolipid-enriched microdomain) is tyrosine phosphorylated and recruits the kinase Csk, leading to increased phosphorylation of the Y505 site, which inhibits Lck activity. In response to TCR stimulation, these modifications are lost. By contrast to Cbp/PAG, CD45 dephosphorylates the regulatory tyrosine residue Y505, resulting in an unfolding and activation of the kinase. Cbp/PAG–Csk and CD45 therefore compete in the regulation of Lck. Abbreviations: ITAM, immunoreceptor-based tyrosine activation motifs; LAT, linker for activation of T cells; MHC, major histocompatibility complex; PTK, protein tyrosine kinase; SLP-76, SH2-domain-containing leukocyte protein of 76 kDa; TCR, T-cell receptor; SH2, Src-homology 2; ZAP-70, zeta-associated protein 70.
|
home | search
| glossary
| links
| sitemap | contact
|
Expert Reviews in
Molecular Medicine © Cambridge University
Press ISSN 1462-3994 (Disclaimer
and copyright)
Editorial Office: Centre for Applied Research
in Educational Technologies (CARET), 1st Floor, 16 Mill Lane, Cambridge,
CB2 1SB, UK. Tel: +44 (0)1223 765 375; Fax: +44(0)1223 765 505; E-mail: ermm@caret.cam.ac.uk