Crk adaptor proteins regulate CD3ζ chain phosphorylation and TCR/CD3 down-modulation in activated T cells
| Autor: | Guangyu Dong, Pulak Ranjan Nath, Noah Isakov, Sigal Gelkop, Rachel Kalifa, Yael Babichev |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CD3 Complex T-Lymphocytes T cell CD3 Receptors Antigen T-Cell Down-Regulation Biology Lymphocyte Activation Antibodies src Homology Domains Jurkat Cells Mice 03 medical and health sciences Adapter molecule crk chemistry.chemical_compound Chlorocebus aethiops medicine Animals Humans Phosphorylation Phosphotyrosine ZAP-70 Protein-Tyrosine Kinase ZAP70 T-cell receptor Signal transducing adaptor protein Tyrosine phosphorylation Cell Biology Proto-Oncogene Proteins c-crk Cell biology Molecular Weight Cross-Linking Reagents 030104 developmental biology medicine.anatomical_structure Biochemistry chemistry COS Cells biology.protein Vanadates Protein Binding |
| Zdroj: | Cellular Signalling. 36:117-126 |
| ISSN: | 0898-6568 |
| DOI: | 10.1016/j.cellsig.2017.04.022 |
| Popis: | T cell receptor (TCR) recognition of a peptide antigen in the context of MHC molecules initiates positive and negative cascades that regulate T cell activation, proliferation and differentiation, and culminate in the acquisition of effector T cell functions. These processes are a prerequisite for the induction of specific T cell-mediated adaptive immune responses. A key event in the activation of TCR-coupled signaling pathways is the phosphorylation of tyrosine residues within the cytoplasmic tails of the CD3 subunits, predominantly CD3ζ. These transiently formed phosphotyrosyl epitopes serve as docking sites for SH2-domain containing effector molecules, predominantly the ZAP70 protein tyrosine kinase, which is critical for signal propagation. We found that CrkI and CrkII adaptor proteins also interact with CD3ζ in TCR activated-, but not in resting-, T cells. Crk binding to CD3ζ was independent of ZAP70 and also occurred in ZAP70-deficient T cells. Binding was mediated by Crk-SH2 domain interaction with phosphotyrosine-containing motifs on CD3ζ, via a direct physical interaction, as demonstrated by Far-Western blot. CrkII binding to CD3ζ could also be demonstrated in a heterologous system, where coexpression of a catalytically active Lck was used to phosphorylate the CD3ζ chain. TCR activation-induced Crk binding to CD3ζ resulted in increased and prolonged phosphorylation of CD3ζ, as well as ZAP70 and LAT, suggesting a positive role for CrkI/II binding to CD3ζ in regulation of TCR-coupled signaling pathways. Furthermore, Crk-dependent increased phosphorylation of CD3ζ coincided with inhibition of TCR downmodulation, supporting a positive role for Crk adaptor proteins in TCR-mediated signal amplification. |
| Databáze: | OpenAIRE |
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