Cloning of the human platelet F11 receptor: a cell adhesion molecule member of the immunoglobulin superfamily involved in platelet aggregation

Abstract

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.

Mechanisms of Outside‐in Signaling at the Tight Junction by Junctional Adhesion Molecule A

“…One example consists of the domain comprising the epitope for F11, an antibody for which JAM-A/F11R was originally named. 37 Peptides mimicking part of the distal Ig domain (D1) block both F11 binding to JAM-A and platelet adhesion to endothelial cells. 11 However, these peptides map to a different area on D1 that is distinct from the cisdimerization region, 17 indicating a potentially separate functional domain.…”

Pores in the Sieve and Channels in the Wall: Control of Paracellular Permeability by Junctional Proteins in Endothelial Cells

“…The extracellular segment comprises two Ig-like domains, an amino terminal (VH-type) and a carboxyl terminal (C2-type) ␤-sandwich fold. The same VH-C2 tandem arrangement occurs in human, rat, and cow JAM-1 (68% to 75% sequence identity) (41,55,68,78), as well as in JAM-2 (7) and JAM-3 (18,57), two recently identified molecules with more than 30% identity with JAM-1. These data point to the existence of a family of JAM proteins that share a common VH-C2 structure, as well as the ability to localize at intercellular junctions and possibly to regulate permeability.…”

“…Description of these molecular associations opens several questions. For instance, as thrombin and collagen induce phosphorylation of JAM-1 in platelets (68), possibly due to protein kinase C activation (56), does JAM-1 phosphorylation modulate the associations of JAM-1 with its known intracellular partners? Also, as ZO-1, CASK, and AF-6 all bind JAM-1 in a PDZ-dependent manner, is the binding to JAM-1 mutually exclusive or, alternatively, do distinct complexes coexist at mature junctions?…”

Mechanisms of Reovirus Bloodstream Dissemination

“…Studies in which oncolytic reovirus was delivered intravenously to persons with cancer revealed that virus is largely found in hematopoietic cells, specifically mononuclear cells, granulocytes, and platelets (Adair et al, 2012). Each of these cell types express JAM-A (Martin-Padura et al, 1998;Naik et al, 2001;Sobocka et al, 2000), suggesting that reovirus associates with or infects blood cells to disseminate through the blood to target organs. However, in these studies, virus was delivered directly into the bloodstream by intravenous inoculation.…”