Abl tyrosine kinases are required for infection by Shigella flexneri

Speaker: 伍展弘

Commentator: 何漣漪  教授

Date: 2004/04/14, 15:00~16:00

Place: Room 601

Abstract:

A key step in the pathogenesis of Shigella flexneri is the ability to enter the normally non-phagocytic cells. Small GTPase activation and non-receptor tyrosine kinase phosphorylation are recognized as two major pathways in bacterial internalization. Previously, the tyrosine kinases, Abl and Arg, have been implicated in signaling pathways downstream of growth factor receptors, such as PDGF. The signaling pathways activated during the initial stages of infection by S.flexneri are similar to those involved in growth factor receptor signaling.¹ In this paper, the authors used a specific inhibitor of the Abl family kinases, STI571, to demonstrate that the bacteria uptake in the MEF cell lines is dependent on Abl/Arg expression. Abl is known to be specifically phosphorylated at tyrosine 221 on Crk, resulting in a conformational change.² To demonstrate whether the phosphorylation at Crk-Y221 by Abl is necessary during Shigella infection, they examined the tyrosine phosphorylation levels of the adaptor protein Crk during Shigella infection in cells with or without Abl and Arg. Crk was phosphorylated at various time points during Shigella infection by immunoblotting assay. The data demonstrated that phosphorylation of Crk by the Abl family kinases is an essential step for efficient Shigella internalization. In addition, they also measured the activation of endogenous Rac and Cdc42 during Shigellainfection, and demonstrated that the Abl and Crk kinases mediated the activation of Rac and Cdc42. Finally, the authors used immunofluorescence microscopy to localize Abl, Arg and Crk to the sites of bacterial entry and these data provide further support for a role of these signaling molecules in Shigella internalization. Taken together, these findings reveal a novel role for the Abl tyrosine kinases in Shigella pathogenesis.³

References:

1.     Plattner,R., Kadlec,L., DeMali,K.A., Kazlauskas,A. and Pendergast,A.M. (1999) c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. Genes Dev., 13, 2400-2411.

2.     Feller,S.M., Knudsen,B. and Hanafusa,H. (1994) c-Abl kinase regulates the protein binding activity of c-Crk. EMBO J., 13, 2341-2351.

3.     Burton, E. A., Plattner, R., and Pendergast, A. M. (2003) Abl tyrosine kinases are required for infection by Shigella flexneri. EMBO J., 22, 5471-5479.