Fig. 2

Schematic of integrin αIIbβ3 inside-out signaling in platelets. Soluble agonist (ADP, epinephrine, 5-HT, TXA₂, and thrombin) stimulation of G protein-coupled receptors (GPCRs) triggers PLCβ activation. Collagen-bound vWF/GPIb-IX-V and collagen/GPVI interactions ultimately induce PLCγ activation. PLC hydrolyzes platelet membrane phosphatidylinositol (4,5)-bisphosphate (PI-4,5-P, PIP2) into diacylglycerol (DAG) and inositol (1,4,5)-triphosphate (IP3). IP3 induces Ca²⁺ release. DAG, together with Ca²⁺, activates CalDAG-GEFI and PKC. Activated CalDAG-GEFI along with PKC leads to the shift of Rap1-GDP to Rap1-GTP. Rap1-GTP targets the lipid membrane through farnesylation of its CAAX motif. RIAM functions as a linker between Rap1-GTP and talin, forming a Rap1/RIAM/talin complex. Complex-bound talin interacts with the integrin β3 subunit through the plasma membrane. Binding of talin-H (FERM domain) to the NPLY motif of the β3 tail disrupts the salt bridge between the αIIb and β3 subunits, leading to integrin αIIbβ3 activation, shifting from a bent to an extended conformation. Kindlin binding to the NITY motif of the β3 tail is shown. CIB1 directly binds to the αIIb cytoplasmic tail. ADAP serves as a bridging molecule between kindlin and talin, promoting platelet integrin αIIbβ3 activation