Disruption of T cell signaling networks and development by Grb2 haploid insufficiency

The developmental processes of positive and negative selection in the thymu s shape the T cell antigen receptor (TCR) repertoire and require the integr ation of multiple signaling networks. These networks involve the efficient assembly of macromolecular complexes and ave mediated by multimodular adapt or proteins that permit the functional integration of distinct signaling mo lecules. We show here that decreased expression of the adaptor protein Grb2 in Grb2(+/-) mice weakens TCR-induced c-Jun N-terminal kinase (JNK) and p3 8, but not extracellular signal-regulated kinase (ERK), activation. In turn , this selective effect decreases the ability of thymocytes to undergo nega tive, 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 quantita tive differences in signal strength can alter the balance of downstream sig naling pathways to induce the qualitatively distinct biological outcomes of proliferation, differentiation or apoptosis.