Figure 6.
Schematic of the GPR56 cleavage-dependent signaling pathway. A, collagen III binds to GPR56 NTF, causing conformational changes, including NTF shedding. Exposure of the Stachel tethered agonist results in 7TM domain activation. B, TG2 binds to GPR56 but fails to activate the receptor in the absence of the ECM protein laminin. C, combined binding of TG2 and laminin to GPR56 induces dissociation of GPR56 NTF from its CTF, allowing Stachel to initiate downstream signaling. D, P19 possesses the seven amino acids of the tethered agonist and activates downstream signaling. E, 3-α-DOG binds to part of the orthosteric site of the receptor and activates GPR56 when the other pocket of the ligand binding site is engaged by part of Stachel. Stachel of the noncleavable receptor GPR56H381S is buried by the NTF and therefore cannot be activated by 3-α-DOG.