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Clustering transfers the translocated Escherichia coli receptor into lipid rafts to stimulate reversible activation of c-Fyn.

Hayward, RD; Hume, PJ; Humphreys, D; Phillips, N; Smith, K; Koronakis, V; (2009) Clustering transfers the translocated Escherichia coli receptor into lipid rafts to stimulate reversible activation of c-Fyn. Cell Microbiol , 11 (3) pp. 433-441. 10.1111/j.1462-5822.2008.01265.x.

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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 Tir(Y474) 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 Tir(Y474) and c-Fyn in DRMs rapidly stimulates robust kinase activation both by induced c-Fyn(Y531) dephosphorylation to unlock the inactive state and by reciprocal c-Fyn(Y417) autophosphorylation to promote activity. After signal induction, c-Fyn dissipates and the resting state restored by Csk-dependent phosphorylation of c-Fyn(Y531). 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.

Type: Article
Title: Clustering transfers the translocated Escherichia coli receptor into lipid rafts to stimulate reversible activation of c-Fyn.
Location: England
DOI: 10.1111/j.1462-5822.2008.01265.x
Publisher version: http://dx.doi.org/10.1111/j.1462-5822.2008.01265.x
Language: English
Keywords: Animals, Bacterial Adhesion, Cell Line, Enteropathogenic Escherichia coli, Escherichia coli Proteins, Fibroblasts, Membrane Microdomains, Mice, Phosphorylation, Proto-Oncogene Proteins c-fyn, Receptors, Cell Surface, Signal Transduction, Up-Regulation
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/76175
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