title: Phosphatidylinositol 3'-kinase activity is critical for initiating the oxidative burst and bacterial destruction during CEACAM3-mediated phagocytosis.
abstract: Carcinoembryonic antigen-related cell adhesion molecule 3 (CEACAM3) is an immunoglobulin-related receptor expressed on human granulocytes. CEACAM3 functions as a single chain phagocytotic receptor recognizing gram-negative bacteria such as Neisseria gonorrhoeae, which possess CEACAM-binding adhesins on their surface. The cytoplasmic domain of CEACAM3 contains an immunoreceptor tyrosine-based activation motif (ITAM)-like sequence that is phosphorylated upon receptor engagement. Here we show that the SH2 domains of the regulatory subunit of phosphatidylinositol 3'-kinase (PI3K) bind to tyrosine residue 230 of CEACAM3 in a phosphorylation-dependent manner. PI3K is rapidly recruited and directly associates with CEACAM3 upon bacterial binding as shown by FRET analysis. Although PI3K activity is not required for efficient uptake of the bacteria by CEACAM3-transfected cells or primary human granulocytes, it is critical for the stimulated production of reactive oxygen species by infected phagocytes and the intracellular degradation of CEACAM-binding bacteria. Together, our results highlight the ability of CEACAM3 to coordinate signaling events that not only mediate bacterial uptake, but also trigger the killing of internalized pathogens.
authors.affiliation: Lehrstuhl für Zellbiologie, Universität Konstanz, 78457 Konstanz, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Buntru
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kopp
authors.forename: Maike
authors.initials: M
authors.lastname: Voges
authors.forename: Ronald
authors.initials: R
authors.lastname: Frank
authors.forename: Verena
authors.initials: V
authors.lastname: Bachmann
authors.forename: Christof R
authors.initials: CR
authors.lastname: Hauck
mesh_terms: D018829:Adhesins, Bacterial / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism*; D006069:Gonorrhea / Q000235:genetics / Q000378:metabolism*; D006098:Granulocytes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009344:Neisseria gonorrhoeae / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D018909:src Homology Domains
chemical_list: D018829:Adhesins, Bacterial; D002272:Carcinoembryonic Antigen; D019869:Phosphatidylinositol 3-Kinases; D017382:Reactive Oxygen Species; C075729:CEACAM3 protein, human