title: 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.
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.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: L
authors.initials: L
authors.lastname: Eckmann
authors.forename: M T
authors.initials: MT
authors.lastname: Rudolf
authors.forename: A
authors.initials: A
authors.lastname: Ptasznik
authors.forename: C
authors.initials: C
authors.lastname: Schultz
authors.forename: T
authors.initials: T
authors.lastname: Jiang
authors.forename: N
authors.initials: N
authors.lastname: Wolfson
authors.forename: R
authors.initials: R
authors.lastname: Tsien
authors.forename: J
authors.initials: J
authors.lastname: Fierer
authors.forename: S B
authors.initials: SB
authors.lastname: Shears
authors.forename: M F
authors.initials: MF
authors.lastname: Kagnoff
authors.forename: A E
authors.initials: AE
authors.lastname: Traynor-Kaplan
mesh_terms: D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012480:Salmonella Infections / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007295:Inositol Phosphates; C081651:inositol-1,4,5,6-tetrakisphosphate; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases