Impaired Plasma Membrane Targeting of Grb2–Murine Son of Sevenless (mSOS) Complex and Differential Activation of the Fyn–T Cell Receptor (TCR)-ζ–Cbl Pathway Mediate T Cell Hyporesponsiveness in Autoimmune Nonobese Diabetic Mice

Konstantin Salojin; Jian Zhang; Mark Cameron; Bruce Gill; Guillermo Arreaza; Atsuo Ochi; Terry L Delovitch

doi:10.1084/jem.186.6.887

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Impaired Plasma Membrane Targeting of Grb2–Murine Son of Sevenless (mSOS) Complex and Differential Activation of the Fyn–T Cell Receptor (TCR)-ζ–Cbl Pathway Mediate T Cell Hyporesponsiveness in Autoimmune Nonobese Diabetic Mice

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Impaired Plasma Membrane Targeting of Grb2–Murine Son of Sevenless (mSOS) Complex and Differential Activation of the Fyn–T Cell Receptor (TCR)-ζ–Cbl Pathway Mediate T Cell Hyporesponsiveness in Autoimmune Nonobese Diabetic Mice

Konstantin Salojin, Jian Zhang, Mark Cameron, Bruce Gill, Guillermo Arreaza, Atsuo Ochi and Terry L Delovitch

The Journal of experimental medicine, Vol.186(6), pp.887-897

09/15/1997

DOI: 10.1084/jem.186.6.887

PMID: 9294143

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Abstract

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.

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Title: Subtitle: Impaired Plasma Membrane Targeting of Grb2–Murine Son of Sevenless (mSOS) Complex and Differential Activation of the Fyn–T Cell Receptor (TCR)-ζ–Cbl Pathway Mediate T Cell Hyporesponsiveness in Autoimmune Nonobese Diabetic Mice
Creators: Konstantin Salojin - From the Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada N6G 2V4; and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4
Jian Zhang - From the Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada N6G 2V4; and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4
Mark Cameron - From the Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada N6G 2V4; and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4, From the Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada N6G 2V4; and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4
Bruce Gill - From the Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada N6G 2V4; and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4
Guillermo Arreaza - From the Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada N6G 2V4; and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4
Atsuo Ochi - From the Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada N6G 2V4; and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4
Terry L Delovitch - From the Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada N6G 2V4; and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4, From the Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada N6G 2V4; and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4
Resource Type: Journal article
Publication Details: The Journal of experimental medicine, Vol.186(6), pp.887-897
DOI: 10.1084/jem.186.6.887
PMID: 9294143
ISSN: 0022-1007
eISSN: 1540-9538
Language: English
Date published: 09/15/1997
Academic Unit: Pathology
Record Identifier: 9984047705002771

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