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Volume 271, Number 38, Issue of September 20, 1996 pp. 23431-23437
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Identification of a Bacterial Inhibitor of Protein Kinases
MECHANISM AND ROLE IN HOST CELL INVASION

(Received for publication, March 14, 1996, and in revised form, June 18, 1996)

Stuart A. Berger ^§ , Kevin Rowan , Hamish D. Morrison and Hermann J. Ziltener ^''

From the  Wellesley Hospital Research Institute, Toronto, Ontario, Canada M4Y 1J3, the ^§ Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1X8, the  Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 123, and the ^'' Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 123

We show that Escherichia coli produce a factor that inhibits the activity of tyrosine and serine/threonine protein kinases. The factor is a protein found in the periplasmic compartment and is also secreted into the culture medium. Using a particle concentration fluorescence immunoassay specific for tyrosine kinase activity and inhibition of the tyrosine kinase p56^lck, we purified this factor to apparent homogeneity. Analysis of trypsin-digested fragments by mass spectrometry identified the inhibitor as the bacterial periplasmic protein UDP-sugar hydrolase, an enzyme with potent and nonspecific 5-nucleotidase activity. Overexpression of the enzyme in bacteria leads to coordinate increases in both 5-nucleotidase and p56^lck inhibitory activity, confirming the identity of the inhibitor. The kinase inhibitory activity appears to be due to the formation of adenosine, which we show is inhibitory for p56^lck, cAMP-dependent protein kinase, and casein kinase. Overexpression of UDP-sugar hydrolase leads to an increase in the recovery of enteropathogenic E. coli following infection of HeLa cell monolayers and corresponding alterations in tyrosine-phosphorylated host proteins. These results suggest that UDP-sugar hydrolase may be an important factor affecting host cell function following intracellular bacterial infection.

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