A New Platelet Receptor Specific to Type III Collagen

Abstract

Platelet interaction with type III collagen is mediated by several platelet receptors that recognize specific sequences in collagen. We previously described an octapeptide KP*GEP*GPK within the ␣(1)III-CB4 fragment that binds to platelets and specifically inhibits platelet aggregation induced by type III collagen. In this study, we demonstrated that the octapeptide prevented platelet contact and spreading on type III collagen and subendothelium under static and flow conditions. Platelets adhered to the immobilized octapeptide, and antibodies directed against other platelet collagen receptors (glycoprotein (GP) Ia/IIa, GP IV, p65, p47) did not impair this adhesion. The platelet octapeptide receptor was identified by ligand blotting as a protein doublet with molecular masses of 68 and 72 kDa and does not correspond to any other already known platelet collagen receptors (GP Ia, GP IV GP VI, and p65). Our results indicate that a specific type III collagen receptor, expressed on the platelet surface, is involved in the first stages of platelet type III collagen interaction.Type I and type III collagens are predominant vascular thrombogenic molecules. Platelet interaction with collagen is a complex phenomenon, involving several platelet membrane glycoproteins (1) and nonintegrin receptors (2), with different binding sites on the collagen molecule coming into play in a specific order during the sequential phases of platelet collagen interaction, i.e. platelet contact, spreading, and aggregation. GP 1 Ia/IIa (integrin ␣ 2 /␤ 1 , very late antigen-2) is a major collagen receptor. It binds to type I collagen via specific sequences within the ␣1(I)-CB3 fragment: residues 435-438 (DGEA) 2 (3) and residues 502-516 with an essential GER sequence (4), and within the ␣2(I)-CB4 peptide (5). Platelet GP Ia/IIa binds to the ␣1(III)-CB4 peptide on type III collagen and, more precisely, to a GGPP*GPR sequence (residues 522-528) (6). However, the role of GP Ia/IIa in platelet activation remains poorly understood, as it is not involved in the initial platelet contact (7) and it indirectly affects spleen tyrosine kinase phosphorylation during signal transduction (8). Spleen tyrosine kinase phosphorylation is induced by the binding of platelet GP VI to the GPP* sequences contained in the triple helical structure of collagen (9). Moreover, collagen-related peptides composed of a GPP* sequence repeats, are able to induce platelet aggregation via platelet GP VI (10). The platelet membrane glycoprotein GP IV (11) has been proposed as a collagen receptor, but its role seems to be restricted to type V collagen (12). Finally, Chiang et al. identified p65 as a specific type I collagen receptor that binds the ␣1(I)-CB5 fragment (13-15) and p47, which recognizes type III collagen (16).Previous studies from our laboratory showed that platelets bind to specific sequences of type I (17) and type III collagens (18 -20). In Particular, platelets react with an octapeptide in type III collagen that is located within the ␣1(III)-CB4 fragment (residues 49...

Role for Neutrophil Extracellular Traps (NETs) and Platelet Aggregation in Early Sepsis-induced Hepatic Dysfunction

“…In the liver tissue, sinusoidal endothelial cell damage allows platelets to enter the space of Disse, which contains collagen type 3 (24,25). Within the space of Disse, platelets bind to and form aggregates with the collagen type 3 (26). Such platelet aggregation in the space of Disse has been termed extravasated platelet aggregation.…”

Platelet adhesion signalling and the regulation of thrombus formation

“…Furthermore, in the presence of α2β1-and GPV-blocking antibodies, mouse platelets that possess approximately 20% of the normal levels of GPVI-FcRγ respond to collagen but not to collagen-related peptide (a GPVI-selective ligand, see below) (Poole et al, 1997;Snell et al, 2002). Several additional putative platelet collagen receptors have been reported, including 68 kDa (Monnet et al, 2001;Monnet and Fauvel-Lefeve, 2000) and 65 kDa (Chiang et al, 1997) binding proteins for type III collagen, and a 47 kDa type I collagen-binding species (Chiang et al, 2002). It is unclear whether any of these contribute to platelet signalling, although some may have supporting roles and modulate GPVImediated responses.…”

Therapeutic approaches in arterial thrombosis

“…Interestingly, part of this signaling pathway may be common to GPIba activation, and signals coming from these two receptors contribute to the activation of the receptor function of GP IIb-IIIa and platelet aggregation. Modulation of the GPVI receptor function is becoming an attractive target as platelets from GPVI-deficient animals, human platelets expressing low levels of GPVI, or platelets treated with a GPVI antibody, while unable to support thrombus growth [67][68][69], are nontheless able to adhere on the collagen surface (via a 2 b 1 integrin and potentially another collagen receptor [70]) minimizing the effects on hemostasis [71,72]. GPIba is a high shear rate-dependent thrombosis receptor that affects recruitment of platelets at sites of vascular injury (on the collagen present in the subendothelium and on adhering platelets) with minor impact on venous thrombotic process.…”