Fig. 8.

Proposed model of platelet GPR56 activation in hemostasis. Upon damage to the vessel wall endothelium, the subendothelial connective tissue that contains collagen becomes exposed to circulation. The collagen rapidly recruits and helps to decelerate a few circulating platelets and induces their shape change and activation program. Tethering of platelets is mediated by interaction of collagen-bound vWF and the nonsignaling platelet glycoprotein, GP1b-V-IX. Platelets roll or translocate along the collagen through vWF/GP1b-V-IX interactions. During the rolling phase, we propose that platelet GPR56 interacts with collagen via its NTF PLL domain. Continued rolling of the platelet may provide sufficient shear force to dissociate the collagen-anchored GPR56 NTF from the platelet membrane-associated CTF. The NTF is jettisoned onto collagen, whereas the CTF is rapidly self-activated by tethered agonism to stimulate G13 signaling and induction of platelet shape changes and filopodia protrusion. The collagen-bound GPR56 NTF may become solubilized into the plasma for its clearance (dashed line). Shape change is a prerequisite to platelet spreading, firm adhesion, and the reinforcing signaling events mediated by other collagen receptors, including GPVI/FcRγ and integrin α2β1. Additional circulating platelets are recruited to the growing platelet plug, and secondary hemostasis ensues. GAIN, G protein-coupled receptor autoproteolysis-inducing domain.