期刊
CELLULAR SIGNALLING
卷 23, 期 6, 页码 1009-1016出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2010.11.018
关键词
cAMP; Immune regulation; Protein kinase A; Regulatory T cell; T cell
类别
资金
- Norwegian Functional Genomics Programme (FUGE)
- Research Council of Norway
- Norwegian Cancer Society
- Novo Nordic Foundation Committee
The canonical second messenger CAMP is well established as a potent negative regulator of T cell immune function:Through protein kinase A (PKA) it regulates T cell function at the level of transcription factors, members of the mitogen-activated protein kinase pathway, phospholipases (PLs). Ras homolog (Rho)A and proteins involved in the control of cell cycle progression. Type I PKA is the predominant PKA isoform in T cells. Furthermore, whereas type II PKA is located at the centrosome, type I PKA is anchored close to the T cell receptor (TCR) in lipid rafts by the Ezrin-ERM-binding phosphoprotein of 50 kDa (EBP50)-phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG) scaffold complex. The most TCR-proximal target for type I PKA is C-terminal Src kinase (Csk), which upon activation by raft recruitment and phosphorylation inhibits the Src family tyrosine kinases Lck and Fyn and thus functions to maintain T cell homeostasis. Recently, induction of cAMP levels in responder T cells has emerged as one of the mechanisms by which regulatory T (T-R) cells execute their suppressive action. Thus, the cAMP-type I PKA-Csk pathway emerges as a putative target for therapeutic intervention in autoimmune disorders as well as in cancer, where T-R cell-mediated suppression contributes to suboptimal local immune responses. (C) 2010 Elsevier Inc. All rights reserved.
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