Hayward, Richard D. and Hume, P.J. and Humphreys, D. and Phillips, N. and Smith, K. and Koronakis, V. (2009) Clustering transfers the translocatedEscherichia colireceptor into lipid rafts to stimulate reversible activation of c-Fyn. Cellular Microbiology 11 (3), pp. 433-441. ISSN 1462-5814.
Abstract
Enteropathogenic Escherichia coli (EPEC) mimic a ligand–receptor interaction to induce ‘pedestal-like’ pseudopodia on mammalian cells, providing a tractable system to study tyrosine kinase signalling to the actin cytoskeleton. EPEC delivers its own receptor (Tir), which is engaged by a bacterial surface ligand (intimin). When Tir delivery and activity are uncoupled, intimin-induced Tir clustering stimulates TirY474 phosphorylation by the Src-family kinase (SFK) c-Fyn, triggering actin polymerization and pedestal formation. How c-Fyn specifically targets Tir and is regulated remains unknown. We show that clustering transfers Tir into cholesterol-rich detergent-resistant microdomains (DRMs), a signal prompting transient c-Fyn accumulation at bacterial adhesion sites. Co-clustering of TirY474 and c-Fyn in DRMs rapidly stimulates robust kinase activation both by induced c-FynY531 dephosphorylation to unlock the inactive state and by reciprocal c-FynY417 autophosphorylation to promote activity. After signal induction, c-Fyn dissipates and the resting state restored by Csk-dependent phosphorylation of c-FynY531. These data illustrate a sophisticated mechanism evolved by a pathogen effector to reversibly regulate SFKs, and resolve early interactions at a model receptor initiating tyrosine kinase signalling.
Metadata
| Item Type: | Article |
|---|---|
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Administrator |
| Date Deposited: | 16 May 2013 09:37 |
| Last Modified: | 02 Aug 2023 17:04 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/6786 |
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