Dataset Information

Platelet integrin ?IIb?3: 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 ?IIb?3 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 ?IIb?3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin ?IIb?3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin ?IIb?3 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 ?IIb?3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of ?IIb?3 in particular. Integrin ?IIb?3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin ?IIb?3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin ?IIb?3 and its signaling pathways.

SUBMITTER: Huang J

PROVIDER: S-EPMC6407232 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Huang Jiansong J Li Xia X Shi Xiaofeng X Zhu Mark M Wang Jinghan J Huang Shujuan S Huang Xin X Wang Huafeng H Li Ling L Deng Huan H Zhou Yulan Y Mao Jianhua J Long Zhangbiao Z Ma Zhixin Z Ye Wenle W Pan Jiajia J Xi Xiaodong X Jin Jie J

Journal of hematology & oncology 20190307 1

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. Up ...[more]

PMID: 30845955

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Project description:Essentials peroxisome proliferator-activated receptor γ (PPARγ) agonists inhibit platelet function. PPARγ agonists negatively regulate outside-in signaling via integrin αIIbβ3. PPARγ agonists disrupt the interaction of Gα13 with integrin β3. This is attributed to an upregulation of protein kinase A activity.SummaryBackground Agonists for the peroxisome proliferator-activated receptor (PPARγ) have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists. Objectives Profound effects on thrombus formation led us to suspect a role for PPARγ agonists in the regulation of integrin αIIbβ3 mediated signaling. Both GPVI and GPCR signaling pathways lead to αIIbβ3 activation, and signaling through αIIbβ3 plays a critical role in platelet function and normal hemostasis. Methods The effects of PPARγ agonists on the regulation of αIIbβ3 outside-in signaling was determined by monitoring the ability of platelets to adhere and spread on fibrinogen and undergo clot retraction. Effects on signaling components downstream of αIIbβ3 activation were also determined following adhesion to fibrinogen by Western blotting. Results Treatment of platelets with PPARγ agonists inhibited platelet adhesion and spreading on fibrinogen and diminished clot retraction. A reduction in phosphorylation of several components of αIIbβ3 signaling, including the integrin β3 subunit, Syk, PLCγ2, focal adhesion kinase (FAK) and Akt, was also observed as a result of reduced interaction of the integrin β3 subunit with Gα13. Studies of VASP phosphorylation revealed that this was because of an increase in PKA activity following treatment with PPARγ receptor agonists. Conclusions This study provides further evidence for antiplatelet actions of PPARγ agonists, identifies a negative regulatory role for PPARγ agonists in the control of integrin αIIbβ3 outside-in signaling, and provides a molecular basis by which the PPARγ agonists negatively regulate platelet activation and thrombus formation.

Dataset Information

Platelet integrin ?IIb?3: signal transduction, regulation, and its therapeutic targeting.

Publications

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

Similar Datasets

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