title: Enteropathogenic Escherichia coli use redundant tyrosine kinases to form actin pedestals.
abstract: Enteropathogenic Escherichia coli (EPEC) are deadly contaminants in water and food and induce protrusion of actin-rich membrane pedestals beneath themselves upon attachment to intestinal epithelia. EPEC then causes intestinal inflammation, diarrhea, and, among children, death. Here, we show that EPEC uses multiple tyrosine kinases for formation of pedestals, each of which is sufficient but not necessary. In particular, we show that Abl and Arg, members of the Abl family of tyrosine kinases, localize and are activated in pedestals. We also show that pyrido[2,3-d]pyrimidine (PD) compounds, which inhibit Abl, Arg, and related kinases, block pedestal formation. Finally, we show that Abl and Arg are sufficient for pedestal formation in the absence of other tyrosine kinase activity, but they are not necessary. Our results suggest that additional kinases that are sensitive to inhibition by PD also can suffice. Together, these results suggest that EPEC has evolved a mechanism to use any of several functionally redundant tyrosine kinases during pathogenesis, perhaps facilitating its capacity to infect different cell types. Moreover, PD compounds are being developed to treat cancers caused by dysregulated Abl. Our results raise the possibility that PD may be useful in treating EPEC infections, and because PD affects host and not bacterium, selecting resistant strains may be far less likely than with conventional antibiotics.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Alyson
authors.initials: A
authors.lastname: Swimm
authors.forename: Bettina
authors.initials: B
authors.lastname: Bommarius
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Cheng
authors.forename: Patrick
authors.initials: P
authors.lastname: Reeves
authors.forename: Melanie
authors.initials: M
authors.lastname: Sherman
authors.forename: Darren
authors.initials: D
authors.lastname: Veach
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Kalman
mesh_terms: D008841:Actin Cytoskeleton / Q000201:enzymology* / Q000648:ultrastructure; D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins / Q000032:analysis / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004926:Escherichia coli / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000201:enzymology / Q000628:therapy; D029968:Escherichia coli Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017354:Point Mutation / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal
chemical_list: D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins; C495927:Actr2 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D029968:Escherichia coli Proteins; C078332:Nck protein; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; C115711:PD 173074; D011743:Pyrimidines; D011956:Receptors, Cell Surface; C109287:Tir protein, E coli; C495772:Wasl protein, mouse; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl