TY - JOUR
T1 - CEACAM2 negatively regulates hemi (ITAM-bearing) GPVI and CLEC-2 pathways and thrombus growth in vitro and in vivo
AU - Alshahrani, Musaed M.
AU - Yang, Eunice
AU - Yip, Jana
AU - Ghanem, Simona S.
AU - Abdallah, Simon L.
AU - De Angelis, Anthony M.
AU - O'Malley, Cindy J.
AU - Moheimani, Fatemeh
AU - Najjar, Sonia M.
AU - Jackson, Denise E.
PY - 2014/10/9
Y1 - 2014/10/9
N2 - 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 a 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.
AB - 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 a 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.
UR - http://www.scopus.com/inward/record.url?scp=84907612583&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-04-569707
DO - 10.1182/blood-2014-04-569707
M3 - Article
C2 - 25085348
AN - SCOPUS:84907612583
SN - 0006-4971
VL - 124
SP - 2431
EP - 2441
JO - Blood
JF - Blood
IS - 15
ER -