Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 23, Pages 10620-10625Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0905039107
Keywords
signal transduction; T-cell development; Grb2; tyrosine phosphorylation
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Funding
- National Institutes of Health
- Irene Diamond Foundation
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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.
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