Physical proximity and functional cooperation of glycoprotein 130 and glycoprotein VI in platelet membrane lipid rafts.
Blood Coagulation
/ drug effects
Blood Platelets
/ metabolism
Collagen
/ pharmacology
Cytokine Receptor gp130
/ blood
Hemorheology
Humans
Immunoprecipitation
Janus Kinase 2
/ antagonists & inhibitors
Membrane Microdomains
/ physiology
Phospholipase C gamma
/ blood
Phosphorylation
Platelet Aggregation
/ drug effects
Platelet Membrane Glycoproteins
/ chemistry
Protein Interaction Mapping
Protein Kinase Inhibitors
/ pharmacology
Protein Processing, Post-Translational
STAT3 Transcription Factor
/ blood
STAT3 transcription factor
cytokine receptor GP130
membrane microdomain
platelet activation
platelet membrane glycoproteins
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
05
02
2019
accepted:
28
05
2019
pubmed:
31
5
2019
medline:
21
8
2020
entrez:
31
5
2019
Statut:
ppublish
Résumé
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 (sIL-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 (PLCγ2) in collagen-induced signaling. However, it remains unknown how collagen induces phosphorylation and dimerization of STAT3. We conducted complementary in vitro experiments to show that the IL-6 receptor subunit glycoprotein 130 (GP130) was in physical proximity to the collagen receptor glycoprotein VI (GPVI in membrane lipid rafts of platelets. This proximity allows collagen to induce STAT3 activation and dimerization, and the IL-6-sIL-6Rα complex to activate the kinase Syk and the substrate PLCγ2 in the GPVI signal pathway, resulting in an enhanced platelet response to collagen. Disrupting lipid rafts or blocking GP130-Janus tyrosine kinase (JAK)-STAT3 signaling abolished the cross-activation and reduced platelet reactivity to collagen. 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-GP130-JAK-STAT3 pathway has been identified as a potential target to block this hyperactivity.
Identifiants
pubmed: 31145836
doi: 10.1111/jth.14525
pii: S1538-7836(22)14144-9
doi:
Substances chimiques
IL6ST protein, human
0
Platelet Membrane Glycoproteins
0
Protein Kinase Inhibitors
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
platelet membrane glycoprotein VI
0
Cytokine Receptor gp130
133483-10-0
Collagen
9007-34-5
JAK2 protein, human
EC 2.7.10.2
Janus Kinase 2
EC 2.7.10.2
PLCG2 protein, human
EC 3.1.4.3
Phospholipase C gamma
EC 3.1.4.3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1500-1510Informations de copyright
© 2019 International Society on Thrombosis and Haemostasis.
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