Platelet aggregation induces platelet aggregate stability via SLAM family receptor signaling.
Platelet aggregation is a dynamic entity, capable of directing its own growth and stability via the activation of signaling cascades that lead to the expression and secretion of various secondary agonists. Here we show that the signaling pathways triggered during platelet aggregation include an intrinsic pro-thrombotic activity mediated by 2 homophilic adhesion molecules, CD84 and CD150 (SLAM [signaling lymphocyte activation molecule]), which are tyrosine phosphorylated in a platelet aggregation-dependent fashion. The 2 CD84/SLAM adapter proteins, SAP (SLAM-associated protein) and EAT-2 (EWS-activated transcript-2), were found in platelets; only SAP, however, was found to immunoprecipitate with tyrosine-phosphorylated SLAM. The immobilized extracellular domain of CD84 promoted microaggregate formation, while SAP-deficient platelets demonstrated defective spreading on immobilized CD84, demonstrating a functional role in platelets for SLAM family interactions. Finally, analysis of SLAM-deficient mice revealed an overall defect in platelet aggregation in vitro and a delayed arterial thrombotic process in vivo. The data indicate that signaling of the adhesion molecules in the SLAM family, activated by proximity during aggregation, further stabilize platelet-platelet interactions in thrombosis.
Nanda
Nisha
N
Portola Pharmaceuticals, 270 E Grand Ave, Suite 22, San Francisco, CA 94080, USA.
Andre
Patrick
P
Bao
Ming
M
Clauser
Karl
K
Deguzman
Francis
F
Howie
Duncan
D
Conley
Pamela B
PB
Terhorst
Cox
C
Phillips
David R
DR
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism*; D006023:Glycoproteins / Q000145:classification* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000145:classification* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019000:Phosphotyrosine / Q000378:metabolism; D010974:Platelet Aggregation / Q000502:physiology*; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D000071176:Signaling Lymphocytic Activation Molecule Family; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013927:Thrombosis; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C498970:CD84 protein, human; D006023:Glycoproteins; D007136:Immunoglobulins; D011956:Receptors, Cell Surface; C000604059:SLAMF1 protein, human; C491225:Sh2d1b1 protein, mouse; D000071176:Signaling Lymphocytic Activation Molecule Family; D014157:Transcription Factors; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D019000:Phosphotyrosine