title: CEACAM2 negatively regulates hemi (ITAM-bearing) GPVI and CLEC-2 pathways and thrombus growth in vitro and in vivo.
abstract: Carcinoembryonic antigen-related cell adhesion molecule-2 (CEACAM2) is a cell-surface glycoprotein expressed on blood, epithelial, and vascular cells. CEACAM2 possesses adhesive and signaling properties mediated by immunoreceptor tyrosine-based inhibitory motifs. In this study, we demonstrate that CEACAM2 is expressed on the surface and in intracellular pools of platelets. Functional studies of platelets from Ceacam2(-/-)-deficient mice (Cc2(-/-)) revealed that CEACAM2 serves to negatively regulate collagen glycoprotein VI (platelet) (GPVI)-FcRγ-chain and the C-type lectinlike receptor 2 (CLEC-2) signaling. Cc2(-/-) platelets displayed enhanced GPVI and CLEC-2-selective ligands, collagen-related peptide (CRP), collagen, and rhodocytin (Rhod)-mediated platelet aggregation. They also exhibited increased adhesion on type I collagen, and hyperresponsive CRP and CLEC-2-induced α and dense granule release compared with wild-type platelets. Furthermore, using intravital microscopy to ferric chloride (FeCl3)-injured mesenteric arterioles and laser-induced injury of cremaster muscle arterioles, we herein show that thrombi formed in Cc2(-/-) mice were larger and more stable than wild-type controls in vivo. Thus, CEACAM2 is a novel platelet immunoreceptor that acts as a negative regulator of platelet GPVI-collagen interactions and of ITAM receptor CLEC-2 pathways.
authors.affiliation: Thrombosis and Vascular Diseases Laboratory, Health Innovations Research Institute, School of Medical Sciences, Royal Melbourne Institute of Technology University, Bundoora, VIC, Australia; and.
authors.forename: Musaed M
authors.initials: MM
authors.lastname: Alshahrani
authors.affiliation: Thrombosis and Vascular Diseases Laboratory, Health Innovations Research Institute, School of Medical Sciences, Royal Melbourne Institute of Technology University, Bundoora, VIC, Australia; and.
authors.forename: Eunice
authors.initials: E
authors.lastname: Yang
authors.affiliation: Thrombosis and Vascular Diseases Laboratory, Health Innovations Research Institute, School of Medical Sciences, Royal Melbourne Institute of Technology University, Bundoora, VIC, Australia; and.
authors.forename: Jana
authors.initials: J
authors.lastname: Yip
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH.
authors.forename: Simona S
authors.initials: SS
authors.lastname: Ghanem
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Abdallah
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: deAngelis
authors.affiliation: Thrombosis and Vascular Diseases Laboratory, Health Innovations Research Institute, School of Medical Sciences, Royal Melbourne Institute of Technology University, Bundoora, VIC, Australia; and.
authors.forename: Cindy J
authors.initials: CJ
authors.lastname: O'Malley
authors.affiliation: Thrombosis and Vascular Diseases Laboratory, Health Innovations Research Institute, School of Medical Sciences, Royal Melbourne Institute of Technology University, Bundoora, VIC, Australia; and.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Moheimani
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
authors.affiliation: Thrombosis and Vascular Diseases Laboratory, Health Innovations Research Institute, School of Medical Sciences, Royal Melbourne Institute of Technology University, Bundoora, VIC, Australia; and.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Jackson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; C529518:CLEC-2 protein, mouse; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D024042:Collagen Type I; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D010455:Peptides; D010980:Platelet Membrane Glycoproteins; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases; D051966:Phospholipase C gamma
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