Nature Immunology
2, 29 - 36 (2001)
doi:10.1038/83134
Disruption of T cell signaling networks and development by Grb2 haploid
insufficiencyQian Gong1, Alec M. Cheng2, Antonina M. Akk2, Jose Alberola-Ila3, Guoqing Gong2, Tony Pawson4
& Andrew C. Chan11
Howard Hughes Medical Institute, Washington University
School of Medicine, St. Louis, MO 63110,
USA. 2
Center for Immunology, Division of Rheumatology, Departments
of Medicine and Pathology, Washington University School of Medicine,
St. Louis, MO 63110, USA. 3
California Institute of Technology, Division of Biology
, Pasadena, CA 91125, USA.
4
Samuel Lunenfeld Research Institute, Mount Sinai Hospital
, Toronto, ON M5G1X5, Canada.
Correspondence should be addressed to Andrew C. Chan achan@im.wustl.eduThe developmental processes of positive and negative selection in the thymus
shape the T cell antigen receptor (TCR) repertoire and require the integration
of multiple signaling networks. These networks involve the efficient assembly
of macromolecular complexes and are mediated by multimodular adaptor proteins
that permit the functional integration of distinct signaling molecules. We
show here that decreased expression of the adaptor protein Grb2 in Grb2
+/- mice weakens TCR-induced c-Jun N-terminal kinase
(JNK) and p38, but not extracellular signal−regulated kinase (ERK),
activation. In turn, this selective effect decreases the ability of thymocytes
to undergo negative, but not positive, selection. We also show that there
are differences in the signaling thresholds of the three mitogen-activated
protein kinase (MAPK) families. These differences may provide a mechanism
by which quantitative differences in signal strength can alter the balance
of downstream signaling pathways to induce the qualitatively distinct biological
outcomes of proliferation, differentiation or apoptosis.
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