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: Musaed M Alshahrani, Eunice Yang, Jana Yip, Simona S Ghanem, Simon L Abdallah, Anthony M deAngelis, Cindy J O'Malley, Fatemeh Moheimani, Sonia M Najjar, Denise E Jackson
• Journal: Blood (Blood) Vol. 124 Issue 15 Pg. 2431-41 (Oct 09 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 25085348 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• Antigens, CD
• CD66 antigens
• CLEC-2 protein, mouse
• Carrier Proteins
• Cell Adhesion Molecules
• Collagen Type I
• Intracellular Signaling Peptides and Proteins
• Lectins, C-Type
• Peptides
• Platelet Membrane Glycoproteins
• collagen-related peptide
• platelet membrane glycoprotein VI
• Protein-Tyrosine Kinases
• Syk Kinase
• Syk protein, mouse
• src-Family Kinases
• Phospholipase C gamma

Topics

• Animals
• Antigens, CD (metabolism)
• Blood Platelets (drug effects, metabolism, pathology)
• Carrier Proteins (pharmacology)
• Cell Adhesion (drug effects)
• Cell Adhesion Molecules (deficiency, metabolism)
• Cell Membrane (metabolism)
• Collagen Type I (metabolism)
• Cytoplasmic Granules (drug effects, metabolism)
• Hematopoiesis (drug effects)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Intracellular Space (metabolism)
• Lectins, C-Type (metabolism)
• Mice, Inbred C57BL
• Peptides (pharmacology)
• Phospholipase C gamma (metabolism)
• Phosphorylation (drug effects)
• Platelet Membrane Glycoproteins (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Regional Blood Flow (drug effects)
• Signal Transduction (drug effects)
• Syk Kinase
• Thrombosis (metabolism, pathology)
• src-Family Kinases (metabolism)