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Physical proximity and functional cooperation of glycoprotein 130 and glycoprotein VI in platelet membrane lipid rafts
Author(s) -
Houck Katie L.,
Yuan Hengjie,
Tian Ye,
Solomon Madeleine,
Cramer Drake,
Liu Kitty,
Zhou Zhou,
Wu Xiaoping,
Zhang Jianning,
Oehler Vivian,
Dong Jingfei
Publication year - 2019
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14525
Subject(s) - syk , microbiology and biotechnology , gpvi , chemistry , lipid raft , tyrosine phosphorylation , phosphorylation , signal transduction , platelet activation , glycoprotein 130 , collagen receptor , platelet , platelet membrane glycoprotein , biochemistry , tyrosine kinase , receptor , stat3 , integrin , biology , immunology
Objective Clinical and laboratory studies have demonstrated that platelets become hyperactive and prothrombotic in conditions of inflammation. We have previously shown that the proinflammatory cytokine interleukin ( IL )‐6 forms a complex with soluble IL ‐6 receptor α (s IL ‐6Rα) to prime platelets for activation by subthreshold concentrations of collagen. Upon being stimulated with collagen, the transcription factor signal transducer and activator of transcription ( STAT ) 3 in platelets is phosphorylated and dimerized to act as a protein scaffold to facilitate the catalytic action between the kinase Syk and the substrate phospholipase Cγ2 ( PLC γ2) in collagen‐induced signaling. However, it remains unknown how collagen induces phosphorylation and dimerization of STAT 3. Methods and results We conducted complementary in vitro experiments to show that the IL ‐6 receptor subunit glycoprotein 130 ( GP 130) was in physical proximity to the collagen receptor glycoprotein VI ( GPVI in membrane lipid rafts of platelets. This proximity allows collagen to induce STAT 3 activation and dimerization, and the IL ‐6‐s IL ‐6Rα complex to activate the kinase Syk and the substrate PLC γ2 in the GPVI signal pathway, resulting in an enhanced platelet response to collagen. Disrupting lipid rafts or blocking GP 130‐Janus tyrosine kinase ( JAK )‐ STAT 3 signaling abolished the cross‐activation and reduced platelet reactivity to collagen. Conclusion These results demonstrate cross‐talk between collagen and IL ‐6 signal pathways. This cross‐talk could potentially provide a novel mechanism for inflammation‐induced platelet hyperactivity, so the IL ‐6‐ GP 130‐ JAK ‐ STAT 3 pathway has been identified as a potential target to block this hyperactivity.