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Vol. 15, Issue 8, 3520-3529, August 2004

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Enteropathogenic Escherichia coli Use Redundant Tyrosine Kinases to Form Actin Pedestals

Alyson Swimm ^*, Bettina Bommarius ^*, Yue Li ^*, David Cheng ^*, Patrick Reeves , Melanie Sherman ^*, Darren Veach , William Bornmann , and Daniel Kalman ^* 

^* Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322; Department of Microbiology and Molecular Genetics Graduate Program, Emory University, Atlanta, Georgia 30322; and Memorial Sloan Kettering Cancer Center, New York, New York 10021

Submitted February 3, 2004; Accepted May 10, 2004
Monitoring Editor: Peter Walter

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.

Abbreviations used: CML, chronic myelogenous leukemia; DAPI, 4,6 diamidino-2-phenylindol; EPEC, enteropathogenic E. coli O157:H6; HA, hemagglutinin A; mAb, monoclonal antibody; pAb, polyclonal antibody; PD, pyrido[2,3-d]pyrimidine; p-Tyr, phosphotyrosine; YFP, yellow fluorescent protein.

Online version of this article contains supporting material. Online version is available at www.molbiolcell.org.

Corresponding author. E-mail address: dkalman{at}emory.edu.

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