title: The granulocyte orphan receptor CEACAM4 is able to trigger phagocytosis of bacteria.
abstract: Human granulocytes express several glycoproteins of the CEACAM family. One family member, CEACAM3, operates as a single-chain phagocytic receptor, initiating the detection, internalization, and destruction of a limited set of gram-negative bacteria. In contrast, the function of CEACAM4, a closely related protein, is completely unknown. This is mainly a result of a lack of a specific ligand for CEACAM4. By generating chimeric proteins containing the extracellular bacteria-binding domain of CEACAM3 and the transmembrane and cytoplasmic part of CEACAM4 (CEACAM3/4) we demonstrate that this chimeric receptor can trigger efficient phagocytosis of attached particles. Uptake of CEACAM3/4-bound bacteria requires the intact ITAM of CEACAM4, and this motif is phosphorylated by Src family PTKs upon receptor clustering. Furthermore, SH2 domains derived from Src PTKs, PI3K, and the adapter molecule Nck are recruited and associate directly with the phosphorylated CEACAM4 ITAM. Deletion of this sequence motif or inhibition of Src PTKs blocks CEACAM4-mediated uptake. Together, our results suggest that this orphan receptor of the CEACAM family has phagocytic function and prompt efforts to identify CEACAM4 ligands.
authors.affiliation: *Lehrstuhl für Zellbiologie and Konstanz Research School Chemical Biology, Universität Konstanz, Germany; and Division of Experimental Pathology, Institute of Pathology, University of Bern, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Delgado Tascón
authors.affiliation: *Lehrstuhl für Zellbiologie and Konstanz Research School Chemical Biology, Universität Konstanz, Germany; and Division of Experimental Pathology, Institute of Pathology, University of Bern, Switzerland.
authors.forename: Jonas
authors.initials: J
authors.lastname: Adrian
authors.affiliation: *Lehrstuhl für Zellbiologie and Konstanz Research School Chemical Biology, Universität Konstanz, Germany; and Division of Experimental Pathology, Institute of Pathology, University of Bern, Switzerland.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kopp
authors.affiliation: *Lehrstuhl für Zellbiologie and Konstanz Research School Chemical Biology, Universität Konstanz, Germany; and Division of Experimental Pathology, Institute of Pathology, University of Bern, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Scholz
authors.affiliation: *Lehrstuhl für Zellbiologie and Konstanz Research School Chemical Biology, Universität Konstanz, Germany; and Division of Experimental Pathology, Institute of Pathology, University of Bern, Switzerland.
authors.forename: Mario P
authors.initials: MP
authors.lastname: Tschan
authors.affiliation: *Lehrstuhl für Zellbiologie and Konstanz Research School Chemical Biology, Universität Konstanz, Germany; and Division of Experimental Pathology, Institute of Pathology, University of Bern, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kuespert
authors.affiliation: *Lehrstuhl für Zellbiologie and Konstanz Research School Chemical Biology, Universität Konstanz, Germany; and Division of Experimental Pathology, Institute of Pathology, University of Bern, Switzerland christof.hauck@uni-konstanz.de.
authors.forename: Christof R
authors.initials: CR
authors.lastname: Hauck
mesh_terms: D000595:Amino Acid Sequence; D001419:Bacteria / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry; D006098:Granulocytes / Q000378:metabolism*; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism; D010587:Phagocytosis; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D015398:Signal Transduction; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C000597331:CEACAM4 protein, human; D002272:Carcinoembryonic Antigen; D019000:Phosphotyrosine; D019061:src-Family Kinases
keywords: ITAM; Src kinase; tyrosine phosphorylation