期刊
MOLECULAR IMMUNOLOGY
卷 46, 期 11-12, 页码 2167-2177出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2009.04.032
关键词
CD45; DOK-1; JAKs; STATs; T-cells; Negative regulation
资金
- Natural Science and Engineering Research Council of Canada [GP0183691]
- Canadian Institute of Health Research [MOP82807]
It has been extensively documented that CD45 positively regulates T cell receptor-mediated signaling through the activation of Src-family kinases. The mechanism whereby CD45 negatively regulates the JAK/STAT pathway, however, has not been fully elucidated. Here we describe the mechanism by which CD45 negatively regulates the JAK/STAT pathway through the recruitment of the inhibitory molecule Downstream of Kinase 1 (DOK-1) in hematopoietic cells. We present evidences that CD45 recruits DOK-1 to associate with tyrosine-phosphorylated DOK-1, and that the DOK-1-Y296F mutant completely abrogates its interaction with CD45. Moreover, CD45 expression is required for DOK-1 targeting to the plasma membrane in response to anti-CD3 stimulation. Functional studies further showed that stable expression of DOK-1 in K562 cells markedly decreased both JAK-2 and STAT-3/5 phosphorylation following IL-3 and IFN-alpha stimulation. Likewise, stable expression of DOK-1 in Jurkat cells significantly decreased JAK-2 phosphotylation. Similarly, both IL-3 and IFN-alpha-induced JAK-2 phosphorylations were significantly increased in CD45 deficient Jurkat cells. Consistently, silencing of the DOK-1 gene resulted in rescue of MAP kinases and JAKs activities in CD45 positive Jurkat cells. Accordingly, CD45 recruits adaptor DOK-1 to the proximal plasma membrane to serve as a downstream effector, resulting in negative regulation of the JAK/STAT signaling pathway. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.
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