SummaryThe F11 receptor (F11R) was first identified on the surface of human platelets as a target for a stimulatory monoclonal antibody (M.Ab.F11) that induces secretion, followed by exposure of fibrinogen receptors and aggregation. Cloning of the gene of F11R has revealed that this protein is a cell adhesion molecule (CAM), a member of the Ig superfamily and an ortholog of the murine protein called junctional adhesion molecule (JAM). The present study has identified two domains through which M.Ab.F11 triggers a platelet response culminating with aggregation. M.Ab.F11-mediated platelet adhesion, and the potentiation of collagen and ADP-induced platelet aggregation by M.Ab.F11, were found to involve the same two domains. A F11R recombinant protein (sF11R) completely inhibited platelet aggregation, adhesion and potentiation induced by M.Ab.F11, indicative that the active conformation of the external domain of F11R is present in the soluble, secreted recombinant protein. Furthermore, a specific peptide containing the sequence of the N-terminal amino acids S-1 to C-23 of F11R, and a peptide with the sequence of K-70 to C-82 in the 1st immunoglobulin-like (Ig) fold of F11R, both inhibited M.Ab.F11-induced aggregation, adhesion and potentiation of the aggregation of human platelets. Modeling of the 3D structure of the extracellular domain of the human platelet F11R suggests that these two regions form an active site within the conformation of this CAM. The sequence of these functional domains of F11R (in the N-terminus and 1st Ig-fold) provide the basis for new drug development in the treatment of certain types of thrombocytopenia and inflammatory thrombosis.
This study demonstrates that the human platelet F11 receptor (F11R) functions as an adhesion molecule, and this finding is confirmed by the structure of the protein as revealed by molecular cloning. The F11R is a 32-/35-kd protein duplex that serves as the binding site through which a stimulatory monoclonal antibody causes platelet aggregation and granule secretion. A physiological role for the F11R protein was demonstrated by its phosphorylation after the stimulation of platelets by thrombin and collagen. A pathophysiological role for the F11R was revealed by demonstrating the presence of F11R-antibodies in patients with thrombocytopenia. Adhesion of platelets through the F11R resulted in events characteristic of the action of cell adhesion molecules (CAMs). To determine the structure of this protein, we cloned the F11R cDNA from human platelets. The predicted amino acid sequence demonstrated that it is an integral membrane protein and an immunoglobulin superfamily member containing 2 extracellular C2-type domains. The structure of the F11R as a member of a CAM family of proteins and its activity in mediating adhesion confirm each another. We conclude that the F11R is a platelet-membrane protein involved in 2 distinct processes initiated on the platelet surface. The first is antibody-induced platelet aggregation and secretion that are dependent on both the FcγRII and the GPIIb/IIIa integrin and that may be involved in pathophysiological processes associated with certain thrombocytopenias. The second is an F11R-mediated platelet adhesion that is not dependent on either the FcγRII or the fibrinogen receptor and that appears to play a role in physiological processes associated with platelet adhesion and aggregation.
Plasma F11R is independently associated with the presence and severity of angiographically defined CAD. By virtue of its strong correlation to plasma TNF-alpha, F11R may be an important mediator of the effects of inflammation on the vessel wall. Strategies that block F11R may represent a novel approach to the treatment of human atherosclerosis.
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