D-myo-inositol 1,4,5,6-tetrakisphosphate produced in human intestinal epithelial cells in response to Salmonella invasion inhibits phosphoinositide 3-kinase signaling pathways

Lars Eckmann, Marco T. Rudolf, Andrzej Ptasznik, Carsten Schultz, Tao Jiang, Nora Wolfson, Roger Tsien, Joshua Fierer, Stephen B. Shears, Martin F. Kagnoff, Alexis E. Traynor-Kaplan

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Several inositol-containing compounds play key roles in receptor- mediated cell signaling events. Here, we describe a function for a specific inositol polyphosphate, D-myo-inositol 1,4,5,6-tetrakisphosphate [Ins(1,4,5,6)P4], that is produced acutely in response to a receptor- independent process. Thus, infection of intestinal epithelial cells with the enteric pathogen Salmonella, but not with other invasive bacteria, induced a multifold increase in Ins(1,4,5,6)P4 levels. To define a specific function of Ins(1,4,5,6)P4, a membrane-permeant, hydrolyzable ester was used to deliver it to the intracellular compartment, where it antagonized epidermal growth factor (EGF)-induced inhibition of calcium-mediated chloride (Cl-) secretion (CaMCS) in intestinal epithelia. This EGF function is likely mediated through a phosphoinositide 3-kinase (PtdIns3K)-dependent mechanism because the EGF effects are abolished by wortmannin, and three different membrane-permeant esters of the PtdIns3K product phosphatidylinositol 3,4,5- trisphosphate mimicked the EGF effect on CaMCS. We further demonstrate that Ins(1,4,5,6)P4 antagonized EGF signaling downstream of PtdIns3K because Ins(1,4,5,6)P4 interfered with the PtdInsP3 effect on CaMCS without affecting PtdIns3K activity. Thus, elevation of Ins(1,4,5,6)P4 in Salmonella-infected epithelia may promote Cl- flux by antagonizing EGF inhibition mediated through PtdIns3K and PtdInsP3.

Original languageEnglish (US)
Pages (from-to)14456-14460
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number26
DOIs
StatePublished - Dec 23 1997
Externally publishedYes

ASJC Scopus subject areas

  • General

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