期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 28, 期 7, 页码 2470-2480出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01505-07
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资金
- NCI NIH HHS [P30-CA14599, P30 CA014599] Funding Source: Medline
- NIAMS NIH HHS [R01 AR049775, K02 AR049047, R01AR049775] Funding Source: Medline
It has previously been shown that E3 ubiquitin ligase Casitas B-lineage lymphoma-b (Cbl-b) negatively regulates T-cell activation, but the molecular mechanism(s) underlying this inhibition is not completely defined. In this study, we report that the loss of Cbl-b selectively results in aberrant activation of NF-kappa B upon T-cell antigen receptor (TCR) ligation, which is mediated by phosphatidylinositol 3-kinase (PI3-K)/Akt and protein kinase C-theta (PKC-theta). TCR-induced hyperactivation of Akt in the absence of Cbl-b may potentiate the formation of caspase recruitment domain-containing membrane-associated guanylate kinase protein I (CARMA1)-B-cell lymphoma/leukemia 10 (Bcl10)-mucosa-associated lymphatic tissue 1(MALT1) (CBM) complex, which appears to be independent of PKC-theta. Cbl-b associates with PKC-theta upon TCR stimulation and regulates TCR-induced PKC-theta activation via Vav-1, which couples PKC-theta to PI3-K and allows it to be phosphorylated. PKC-theta then couples I kappa B kinases (IKKs) to the CBM complex, resulting in the activation of the IKK complex. Therefore, our data provide the first evidence to demonstrate that the down-regulation of TCR-induced NF-kappa B activation by Cbl-b is mediated coordinately by both Akt-dependent and PKC-theta-dependent signaling pathways in primary T cells.
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