Figure 2.

Mechanism of aIIbβ3 inside-out signaling. On platelets, the collagen-GPVI interaction induces PLCy2 activation while ADP-P2Y₁, TxA2-TP and thrombin-PAR interactions induce PLCβ activation. Activated PLC then generates IP3 and DAG, which mobilize intracellular calcium and activate PKC, respectively, leading to CalDAG-GEFI activation. The ADP-P2Y₁₂ interaction activates PI3K which inhibits Rasa3. Activated CalDAG-GEFI and inhibited Rasa3 induce Rap1b activation, which binds to talin, thereby enabling activation of integrin αIIb(33 and a change in its conformation. Kindlin-3, by enhancing the interaction between talin and αIIb(33, also participates in αIIb(33 activation. ADP: adenosine diphosphate; ATP: adenosine triphosphate; CalDAG-GEFI: calcium and diacylglycerol-regulated guanine nucleotide exchange factor I; DAG: diacylglycerol; GPVI: glycoprotein VI; GTP: guanosine triphosphate; IP3: inositol-1,4,5-triphosphate; PAR: protease-activated receptor; PI3K: phosphoinositide 3-kinase; PKC: protein kinase C; PLC: phospholipase C; RAP1b: Ras-related protein 1b; Rasa3: Ras GTPase-activating protein 3; TP: thromboxane and prostaglandin receptor; TxA2: thromboxane A2.