title: Grb2 functions at the top of the T-cell antigen receptor-induced tyrosine kinase cascade to control thymic selection.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Ihn Kyung
authors.initials: IK
authors.lastname: Jang
authors.forename: Jinping
authors.initials: J
authors.lastname: Zhang
authors.forename: Yungping J
authors.initials: YJ
authors.lastname: Chiang
authors.forename: Hemanta K
authors.initials: HK
authors.lastname: Kole
authors.forename: Darran G
authors.initials: DG
authors.lastname: Cronshaw
authors.forename: Yongrui
authors.initials: Y
authors.lastname: Zou
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
mesh_terms: 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
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490894:Gab2 protein, mouse; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases