Grb2 functions at the top of the T-cell antigen receptor-induced tyrosine kinase cascade to control thymic selection.
Grb2 is an adaptor molecule that mediates Ras-MAPK activation induced by various receptors. Here we show that conditional ablation of Grb2 in thymocytes severely impairs both thymic positive and negative selections. Strikingly, the mutation attenuates T-cell antigen receptor (TCR) proximal signaling, including tyrosine phosphorylation of multiple signaling proteins and Ca(2+) influx. The defective TCR signaling can be attributed to a marked impairment in Lck activation. Ectopic expression of a mutant Grb2 composed of the central SH2 and the C-terminal SH3 domains in Grb2(-/-) thymocytes fully restores thymocyte development. Thus, Grb2 plays a pivotal role in both thymic positive and negative selection. It amplifies TCR signaling at the top end of the tyrosine phosphorylation cascade via a scaffolding function.
Jang
Ihn Kyung
IK
Department of Microbiology and Immunology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Zhang
Jinping
J
Chiang
Yungping J
YJ
Kole
Hemanta K
HK
Cronshaw
Darran G
DG
Zou
Yongrui
Y
Gu
Hua
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C490894:Gab2 protein, mouse; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases