The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/9/887/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 6, September 15, 1997 887-897

Articles

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

Konstantin Salojin*, Jian Zhang*, Mark Cameron*,{ddagger}, Bruce Gill*, Guillermo Arreaza*, Atsuo Ochi{ddagger}, and Terry L. Delovitch*,{ddagger}

From the * Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada N6G 2V4; and {ddagger} Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4

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-{zeta}–Cbl pathway, which may account for the impaired recruitment of ZAP70 to membrane-bound TCR-{zeta}; (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-{gamma}1 from the TCR-{zeta}–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.

Address correspondence to Dr. T.L. Delovitch, Director, Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, 1400 Western Road, London, Ontario N6G 2V4, Canada. Phone: 519-663-3972; FAX: 519-663-3847; E-mail: del{at}rri.on.ca

1 Abbreviations used in this paper: GRF, GDP releasing factor; GST, glutathione S-transferase; IDDM, insulin-dependent diabetes mellitus; MAPK, mitogen-activated protein kinase; mSOS, murine son of sevenless; NOD, nonobese diabetic; PLC, phospholipase C; PTK, protein tyrosine kinase; p-Tyr, phosphotyrosine; SH, Src homology domain.

K. Salojin and J. Zhang contributed equally to this work.


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