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

  • Hayward R
  • Hume P
  • Humphreys D
 et al. 
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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.

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  • Daniel HumphreysUniversity of Cambridge

  • Richard D. Hayward

  • Peter J. Hume

  • Neil Phillips

  • Katherine Smith

  • Vassilis Koronakis

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