Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting

Abstract

Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbβ3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbβ3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbβ3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbβ3 in particular. Integrin αIIbβ3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbβ3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbβ3 and its signaling pathways.

Keywords: Integrin αIIbβ3; Kindlin; Signal transduction; Talin; Therapeutic targeting; Transmembrane proteins.

Fig. 1

Domains and binding sites of talin. Talin-H comprises an atypical FERM domain containing F0, F1, F2, and F3 domains. Talin-R is composed of 13 amphipathic helical bundle domains (R1-R13, containing 62 α-helices), each consisting of four or five α-helices. A calpain-II cleavage site lies between talin-H and talin-R. Binding sites for interacting proteins are indicated by horizontal lines

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

Fig. 3

Schematic of integrin αIIbβ3 outside-in signaling in platelets. Following ligand binding to the extracellular domain of integrin αIIbβ3, integrin αIIbβ3 clustering promotes Src activation by autophosphorylation. Calpain cleaves the integrin β3 cytoplasmic tail and leads to disassociation of partly active Src from the integrin β3 tail. Src phosphorylates and supports the activation of a wide range of enzymes and signaling proteins, such as FAK, Syk kinase, RhoGAP, Rac-GEFs, RhoGEFs, and PI3K. Gα13, talin, kindlin, tensin, and vinculin provide the necessary links between the integrin β3 cytoplasmic tail and actin. Kindlin can directly couple integrin β3 to the actin cytoskeleton via the ILK/PINCH/parvin complex

Fig. 4

Amino acid sequence of the C-terminal tail of integrin β3, highlighting interaction sites involved in integrin αIIbβ3 bidirectional signaling. Calpain cleavage sites are indicated by arrows. Phosphorylatable amino acid residues (tyrosine and threonine) are labeled in red. Positions of the horizontal lines indicate sites on the integrin β3 cytoplasmic tail that interact with cytoplasmic signaling proteins