Signaling-mediated cooperativity between glycoprotein Ib-IX and protease-Activated receptors in thrombin-induced platelet activation

Brian Estevez, Kyungho Kim, M. Keegan Delaney, Aleksandra Stojanovic-Terpo, Bo Shen, Changgeng Ruan, Jaehyung Cho, Zaverio M. Ruggeri, Xiaoping Du

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Thrombin-induced cellular response in platelets not only requires protease-Activated receptors (PARs), but also involves another thrombin receptor, the glycoprotein Ib-IX complex (GPIb-IX). It remains controversial how thrombin binding to GPIb-IX stimulates platelet responses. It wasproposed that GPIb-IX serves as a dock that facilitates thrombin cleavage of protease-Activated receptors, but there are also reports suggesting that thrombin binding to GPIb-IX induces platelet activation independent of PARs. Here we show that GPIb is neither a passive thrombin dock nor a PAR-independent signaling receptor. We demonstrate a novel signaling-mediated cooperativity between PARs and GPIb-IX. Low-dose thrombin-induced PAR-dependent cell responses require the cooperativity of GPIb-IX signaling, and conversely, thrombin-induced GPIb-IX signaling requires cooperativity of PARs. This mutually dependent cooperativity requires a GPIb-IX-specific 14-3-3-Rac1-LIMK1 signaling pathway, and activation of this pathway also requires PAR signaling. The cooperativity between GPIb-IX signaling and PAR signaling thus drives platelet activation at low concentrations of thrombin, which are important for in vivo thrombosis.

Original languageEnglish
Pages (from-to)626-636
Number of pages11
JournalBlood
Volume127
Issue number5
DOIs
StatePublished - Feb 4 2016

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