IngentaConnect Cell invasion and IL-8 production pathways initiated by YadA of Y...

Authors: Julia Eitel; Tanja Heise; Ulla Thiesen¹; Petra Dersch¹

Source: Cellular Microbiology, Volume 7, Number 1, January 2005 , pp. 63-77(15)

Abstract:

Summary

The YadA protein of Yersinia pseudotuberculosis promotes tight adhesion and invasion into mammalian cells through bgr

₁-integrins. In this work, we demonstrate that YadA also triggers the production of interleukin-8 (IL-8) in host cells and we identify intracellular signal transduction mechanisms involved in YadA-initiated cell invasion and/or IL-8 synthesis. Tyrosine protein kinases, including the focal adhesion kinase (FAK) and c-Src, as well as the small GTPase Ras, were shown to play a significant role in both YadA-promoted cell processes. YadA-mediated cell contact led to autophosphorylation of FAK at position Tyr397 and induced GTP-loading of Ras. Furthermore, IL-8 production and invasion induced by YadA were strongly reduced in FAK- and c-Src-deficient cells and in cells overexpressing dominant interfering forms of FAK, c-Src or Ras. We also demonstrate that YadA activates the Ras-dependent Raf–MEK1/2–ERK1/2 pathway and mitogen-activated protein kinases (MAPKs) p38 and JNK. Moreover, inhibition of ERK1/2 by pharmacological agents or overexpression of dominant negative FAK, c-Src or Ras abrogated IL-8 release, whereas invasion remained unaffected. In contrast, actin polymerization and phosphatidylinositol 3-kinase (PI3K) activity is essential for YadA-promoted cell entry, but not for cytokine secretion. We conclude that YadA triggers FAK–Src complex formation and subsequent Ras activation, which leads to the stimulation of MAPKs-dependent IL-8 production or to PI3K-dependent invasion.

Document Type: Research article

DOI: 10.1111/j.1462-5822.2004.00434.x

Affiliations: 1: Junior Research Group 6, Robert Koch Institut, Nordufer 20, 13353 Berlin, Germany.

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Cell invasion and IL-8 production pathways initiated by YadA of Yersinia pseudotuberculosis require common signalling molecules (FAK, c-Src, Ras) and distinct cell factors