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.

Ibrutinib Suppresses Early Megakaryopoiesis but Enhances Proplatelet Formation

“…Platelets play important roles in primary hemostasis and thrombosis, as well as in inflammation, the immune response, and tumor cell proliferation. 1,2 Megakaryocytes (MKs) are terminally differentiated hematopoietic cells that are responsible for platelet production. The continuous developmental process by which hematopoietic stem cells (HSCs) give rise to MKs is known as megakaryopoiesis.…”

“…Integrin αIIbβ3 is expressed at a high level exclusively in MKs and platelets. 2 Integrin αIIbβ3 bidirectional signaling plays a central role in MK and platelet functions and is therefore critical for hemostasis and arterial thrombosis. In addition, integrin αIIbβ3 itself and its bidirectional signaling play a role in proplatelet formation (PPF).…”

Tetraspanins: integrating cell surface receptors to functional microdomains in homeostasis and disease

“…Tetraspanin CD9 is also expressed on platelets in which it is the most abundant tetraspanin localized at the surface [43]. Among other partners, it interacts with αIIbβ3 integrin [44], which is a receptor for fibrinogen and the dominant integrin on platelets [45]. Interestingly, JAM-A has been demonstrated to interact with both CD9 and with αIIbβ3 integrin in platelets [46], which suggests that similar to endothelial cells, a ternary JAM-A-CD9-β3 integrin complex might exist in platelets.…”

Blood group‐related antigen Ley on human platelets and its involvement in platelet aggregation via a possible interaction with CD61

“…As fibrinogen attaches to platelets, platelet aggregation and subsequent hemostasis are promoted. 20 The proteins mentioned above are all candidates for Le y modification or its interaction partners. These proteins could be effector molecules for the Le y antigen that could lead to the modulation of platelet functions.…”