Impaired plasma membrane targeting of Grb2-murine son of sevenless (mSOS) complex and differential activation of the Fyn-T cell receptor (TCR)-zeta-Cbl pathway mediate T cell hyporesponsiveness in autoimmune nonobese diabetic mice
| Autor: | Atsuo Ochi, B. M. Gill, Jian Zhang, Mark J. Cameron, G A Arreaza, Terry L. Delovitch, Konstantin V. Salojin |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
MAPK/ERK pathway
T cell T-Lymphocytes Ubiquitin-Protein Ligases Immunology Receptors Antigen T-Cell Son of Sevenless Nod Proto-Oncogene Proteins c-fyn Article Autoimmune Diseases Mice FYN Mice Inbred NOD Proto-Oncogene Proteins medicine Immunology and Allergy Animals Guanine Nucleotide Exchange Factors Proto-Oncogene Proteins c-cbl Phosphorylation Cytoskeleton NOD mice Adaptor Proteins Signal Transducing GRB2 Adaptor Protein Mice Inbred BALB C biology ZAP70 T-cell receptor Cell Membrane Membrane Proteins Proteins Articles Mice Inbred C57BL medicine.anatomical_structure Diabetes Mellitus Type 1 Self Tolerance Cancer research biology.protein ras Proteins Tyrosine Female ras Guanine Nucleotide Exchange Factors Signal Transduction |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 0022-1007 |
| Popis: | Nonobese diabetic (NOD) mouse thymocytes are hyporesponsive to T cell antigen receptor (TCR)-mediated stimulation of proliferation, and this T cell hyporesponsiveness may be causal to the onset of autoimmune diabetes in NOD mice. We previously showed that TCR-induced NOD T cell hyporesponsiveness is associated with a block in Ras activation and defective signaling along the PKC/Ras/MAPK pathway. Here, we report that several sequential changes in TCR-proximal signaling events may mediate this block in Ras activation. We demonstrate that NOD T cell hyporesponsiveness is associated with the (a) enhanced TCR-β–associated Fyn kinase activity and the differential activation of the Fyn–TCR-ζ–Cbl pathway, which may account for the impaired recruitment of ZAP70 to membrane-bound TCR-ζ; (b) relative inability of the murine son of sevenless (mSOS) Ras GDP releasing factor activity to translocate from the cytoplasm to the plasma membrane; and (c) exclusion of mSOS and PLC-γ1 from the TCR-ζ–associated Grb2/pp36–38/ZAP70 signaling complex. Our data suggest that altered tyrosine phosphorylation and targeting of the Grb2/pp36–38/ZAP70 complex to the plasma membrane and cytoskeleton and the deficient association of mSOS with this Grb2-containing complex may block the downstream activation of Ras and Ras-mediated amplification of TCR/CD3-mediated signals in hyporesponsive NOD T cells. These findings implicate mSOS as an important mediator of downregulation of Ras signaling in hyporesponsive NOD T cells. |
| Databáze: | OpenAIRE |
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