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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.

SUBMITTER: Jang IK

PROVIDER: S-EPMC2890815 | biostudies-other | 2010 Jun

REPOSITORIES: biostudies-other

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Grb2 functions at the top of the T-cell antigen receptor-induced tyrosine kinase cascade to control thymic selection.

Jang Ihn Kyung IK Zhang Jinping J Chiang Yungping J YJ Kole Hemanta K HK Cronshaw Darran G DG Zou Yongrui Y Gu Hua H

Proceedings of the National Academy of Sciences of the United States of America 20100524 23

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 m ...[more]

PMID: 20498059

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