Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 phosphorylation. 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.
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PMID:CD45 recruits adapter protein DOK-1 and negatively regulates JAK-STAT signaling in hematopoietic cells. 1948 Dec 64