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A Sticky Story for Signal Transducer and Activator of Transcription 3 in Platelets

2012; Lippincott Williams & Wilkins; Volume: 127; Issue: 4 Linguagem: Inglês

10.1161/circulationaha.112.155366

1524-4539

Karin Chen, Matthew T. Rondina, Andrew S. Weyrich,

Chronic Lymphocytic Leukemia Research

HomeCirculationVol. 127, No. 4A Sticky Story for Signal Transducer and Activator of Transcription 3 in Platelets Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBA Sticky Story for Signal Transducer and Activator of Transcription 3 in Platelets Karin Chen, MD, Matthew T. Rondina, MD and Andrew S. Weyrich, PhD Karin ChenKarin Chen From the Department of Pediatrics (K.C.), Molecular Medicine Program (K.C., M.T.R., A.S.W.), and Department of Internal Medicine (M.T.R., A.S.W.), University of Utah, Salt Lake City, UT. , Matthew T. RondinaMatthew T. Rondina From the Department of Pediatrics (K.C.), Molecular Medicine Program (K.C., M.T.R., A.S.W.), and Department of Internal Medicine (M.T.R., A.S.W.), University of Utah, Salt Lake City, UT. and Andrew S. WeyrichAndrew S. Weyrich From the Department of Pediatrics (K.C.), Molecular Medicine Program (K.C., M.T.R., A.S.W.), and Department of Internal Medicine (M.T.R., A.S.W.), University of Utah, Salt Lake City, UT. Originally published24 Dec 2012https://doi.org/10.1161/CIRCULATIONAHA.112.155366Circulation. 2013;127:421–423Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2012: Previous Version 1 The signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic protein that, on appropriate signaling, translocates to the nucleus and binds DNA response elements of target genes.1 As a result, STAT3 mediates the transcription of key mediators involved in mitogenesis, cell survival, apoptosis, cell cycle regulation, angiogenesis, and metastasis development.1,2 STAT3 also regulates the transcription of several genes in megakaryocytes that are required for the formation of platelets (Figure).3Download figureDownload PowerPointFigure. Schematic representation of traditional and nontraditional roles of signal transducer and activator of transcription 3 (STAT3) in megakaryocytes and platelets, respectively, as described by Zhou et al5 and reviewed here.Article see p 476As megakaryocytes form platelets, they transfer STAT3 to proplatelet tips. Consequently, STAT3 is found in platelets that circulate in the bloodstream (Figure). The presence of STAT3 in platelets raises the question of whether it regulates functional responses in platelets or is simply a vestigial remnant of megakaryocytes. An argument for the "leftover without function" hypothesis is the anucleate status of platelets: simply stated, with no nucleus and no nuclear DNA there is no place for STAT3 to stick in platelets. The problem with this argument is that "simple" is no longer a common word used to describe platelets. Moreover, why would platelets expend energy to carry a protein that they do not need, especially since previous studies have shown that STAT3 undergoes signal-dependent phosphorylation in these anucleate cytoplasts?4 Well, any doubt regarding why STAT3 is present in platelets has been cleared up. Using a combination of pharmacological and genetic based tools, Zhou et al5 demonstrate that STAT3 affects how platelets stick to one another and extracellular matrices. In addition, the authors put forth a new role for interleukin 6 (IL-6) and its soluble receptor in enhancing platelet aggregation.A major strength of the group's findings is the plethora of evidence presented to make the story stick from men to mice and then back to men. First, they used 2 different types of STAT3 inhibitors to block collagen- and collagen-related peptide-dependent aggregation, as well as the formation of thrombi to a collagen substrate under flow conditions in human platelets. Neutralization of STAT3 also reduced collagen-dependent induction of P-selectin surface expression. STAT3 inhibitors, however, did not block ATP release nor did they dampen aggregation induced by ADP or a thrombin receptor activating peptide. Second, platelets from mice deficient in STAT3 aggregated poorly, had a low level of P-selectin surface expression and calcium influx in response to collagen, and formed smaller thrombi when exposed to a collagen matrix under arterial flow. The same platelets reacted normally to ADP and thrombin receptor activating peptide. Additional studies led to studies implying that glycoprotein VI platelet (GPVI) is the primary collagen receptor on platelets linked to the STAT3 signaling pathway. Finally, Zhou et al5 provided the first evidence that the IL-6 signaling complex can influence platelet function. They found that platelets constitutively express glycoprotein 130, which is capable of interacting with exogenous IL-6 and the soluble IL-6 receptor (IL-6R). Together, but not individually, these IL-6 family members induce STAT3 phosphorylation and enhance collagen-dependent platelet aggregation.A transcription-independent role for STAT3 builds on the growing appreciation that previously characterized transcription factors have diverse, noncanonical functions in platelets.6 In activated platelets, the nuclear factor-κB family member B cell lymphoma 3 interacts with Fyn-related tyrosine kinases to contract fibrin-rich clots.7 Nuclear factor-κB itself also has roles in limiting platelet activation,8 and nuclear factor-κB inhibitors attenuate the formation of lipodia in adherent platelets.9 Much like STAT3, peroxisome proliferator-activated receptor-γ regulates collagen-dependent platelet aggregation that is driven by GPVI.10 Ligand-dependent binding of retinoid X receptor also controls GTP-binding protein Gq function and thereby aggregation responses in platelets.11 Cumulatively, these studies point to the sundry function of proteins that were originally thought to have a sole role in transcription.One of the most intriguing findings of the work of Zhou et al5 is the identification of an IL-6 signaling pathway that links inflammation to thrombosis. In response to inflammatory cues, IL-6 is synthesized and released by various types of nucleated cells. IL-6 exerts its activities through 2 molecules, the IL-6R (also known as IL-6Rα) and glycoprotein 130 (also referred to as IL-6Rβ).12 The IL-6R is either membrane bound or soluble. As its name implies, soluble IL-6R is released into the extracellular milieu where it binds IL-6 and then forms a complex with membranous glycoprotein 130. This unique receptor signaling system, termed "IL-6 trans-signaling,"13 induces cellular activation including STAT3-dependent transcriptional responses. Until now there has been no evidence that IL-6 trans-signaling occurs in platelets. Zhou et al5 demonstrate that, in combination with the soluble IL-6R, IL-6 binds membrane-expressed glycoprotein 130 and primes platelets for collagen-induced cellular activation. This suggests that heightened IL-6 trans-signaling in response to inflammation may enhance thrombus formation in a variety of human diseases, such as rheumatoid arthritis, lupus, and sepsis. Conversely, deficiencies in IL-6 production, which have been reported to occur in common variable immune deficiency,14 may lead to dampened thrombus formation and increased bruising and bleeding that is commonly observed in patients with this syndrome.Selective inhibition of IL-6 trans-signaling has recently received considerable attention for the treatment of cancer, and an IL-6R blocking antibody (tocilizumab) was recently approved for Castelman disease and rheumatoid arthritis (reviewed in References 15 and 16). A STAT3 decoy inhibitor is currently being tested in patients with head and neck cancer, and there is emerging evidence that STAT3 inhibitors may prove useful in treating disorders of cardiac-related inflammation.15,17 Thus, it will be important to consider off-target inhibition of platelet activity, which may be good or bad, when patients are treated with IL-6 trans-signaling and STAT3 inhibitors. Indeed, the authors speculate that inhibition of STAT3 may improve inflammation-induced platelet hyperreactivity and improve the efficacy of aspirin in patients with coronary artery disease. The interplay of IL-6 trans-signaling and STAT3 with GPVI will also have to be pondered as the efficacy of GPVI receptor antagonists are screened in the clinic.18Thrombosis is often linked to inflammation, but the reverse has received little attention until Zhou et al5 unmasked the STAT3 signaling pathway in anucleate platelets.5 Their results challenge existing paradigms and, in doing so, reveal that we should never underestimate the resolve of platelets to use previously described nuclear-based systems in alternative ways. Identification of a 3-way bridge among IL-6 trans-signaling, STAT3, and GPVI that courses to aggregation adds to the fascinating biology of platelets (Figure). It also creates a sticky story for STAT3 in platelets, and potentially the cytoplasm of nucleated cells, with clinical implications for human disease.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Andrew S. Weyrich, PhD, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112. E-mail [email protected]References1. Reich NC, Liu L. Tracking STAT nuclear traffic.Nat Rev Immunol. 2006; 6:602–612.CrossrefMedlineGoogle Scholar2. Yue P, Turkson J. Targeting STAT3 in cancer: how successful are we?Expert Opin Investig Drugs. 2009; 18:45–56.CrossrefMedlineGoogle Scholar3. Drachman JG, Sabath DF, Fox NE, Kaushansky K. Thrombopoietin signal transduction in purified murine megakaryocytes.Blood. 1997; 89:483–492.CrossrefMedlineGoogle Scholar4. Tibbles HE, Vassilev A, Wendorf H, Schonhoff D, Zhu D, Lorenz D, Waurzyniak B, Liu XP, Uckun FM. Role of a JAK3-dependent biochemical signaling pathway in platelet activation and aggregation.J Biol Chem. 2001; 276:17815–17822.CrossrefMedlineGoogle Scholar5. Zhou Z, Gushiken FC, Bolgiano D, Salsbery BJ, Aghakasiri N, Jing N, Wu X, Vijayan KV, Rumbaut RE, Adachi R, Lopez JA, Dong JF. Signal transducer and activator of transcription 3 (STAT3) regulates collagen-induced platelet aggregation independently of its transcription factor activity.Circulation. 2013; 127:476–485.LinkGoogle Scholar6. Spinelli SL, Maggirwar SB, Blumberg N, Phipps RP. Nuclear emancipation: a platelet tour de force.Sci Signal. 2010; 3:pe37.CrossrefMedlineGoogle Scholar7. Weyrich AS, Dixon DA, Pabla R, Elstad MR, McIntyre TM, Prescott SM, Zimmerman GA. Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets.Proc Natl Acad Sci USA. 1998; 95:5556–5561.CrossrefMedlineGoogle Scholar8. Gambaryan S, Kobsar A, Rukoyatkina N, Herterich S, Geiger J, Smolenski A, Lohmann SM, Walter U. Thrombin and collagen induce a feedback inhibitory signaling pathway in platelets involving dissociation of the catalytic subunit of protein kinase A from an NFkappaB-IkappaB complex.J Biol Chem. 2010; 285:18352–18363.CrossrefMedlineGoogle Scholar9. Spinelli SL, Casey AE, Pollock SJ, Gertz JM, McMillan DH, Narasipura SD, Mody NA, King MR, Maggirwar SB, Francis CW, Taubman MB, Blumberg N, Phipps RP. Platelets and megakaryocytes contain functional nuclear factor-kappaB.Arterioscler Thromb Vasc Biol. 2010; 30:591–598.LinkGoogle Scholar10. Moraes LA, Spyridon M, Kaiser WJ, Jones CI, Sage T, Atherton RE, Gibbins JM. Non-genomic effects of PPARgamma ligands: inhibition of GPVI-stimulated platelet activation.J Thromb Haemost. 2010; 8:577–587.CrossrefMedlineGoogle Scholar11. Moraes LA, Swales KE, Wray JA, Damazo A, Gibbins JM, Warner TD, Bishop-Bailey D. Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets.Blood. 2007; 109:3741–3744.CrossrefMedlineGoogle Scholar12. Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions.Clin Sci. 2012; 122:143–159CrossrefMedlineGoogle Scholar13. Rose-John S, Neurath MF. IL-6 trans-signaling: the heat is on.Immunity. 2004; 20:2–4.CrossrefMedlineGoogle Scholar14. Cunningham-Rundles C, Radigan L, Knight AK, Zhang L, Bauer L, Nakazawa A. TLR9 activation is defective in common variable immune deficiency.J Immunol. 2006; 176:1978–1987.CrossrefMedlineGoogle Scholar15. Sansone P, Bromberg J. Targeting the interleukin-6/Jak/stat pathway in human malignancies.J Clin Oncol. 2012; 30:1005–1014.CrossrefMedlineGoogle Scholar16. Atzeni F, Benucci M, Salli S, Bongiovanni S, Boccassini L, Sarzi-Puttini P. Different effects of biological drugs in rheumatoid arthritis.Autoimmun Rev. December 3, 2012. doi:pii: S1568-9972(12)00278-9. 10.1016/j.autrev.2012.10.020. http://www.journals.elsevier.com/autoimmunity-reviews. Accessed January 8, 2013.Google Scholar17. Lim CP, Fu XY. Multiple roles of STAT3 in cardiovascular inflammatory responses.Prog Mol Biol Transl Sci. 2012; 106:63–73.CrossrefMedlineGoogle Scholar18. Yeung J, Holinstat M. Newer agents in antiplatelet therapy: a review.J Blood Med. 2012; 3:33–42.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Sun J, Zhang M, Chen K, Chen B, Zhao Y, Gong H, Zhao X and Qi R (2018) Suppression of TLR4 activation by resveratrol is associated with STAT3 and Akt inhibition in oxidized low-density lipoprotein-activated platelets, European Journal of Pharmacology, 10.1016/j.ejphar.2018.08.014, 836, (1-10), Online publication date: 1-Oct-2018. Schwertz H, Rowley J, Zimmerman G, Weyrich A and Rondina M (2017) Retinoic acid receptor-α regulates synthetic events in human platelets, Journal of Thrombosis and Haemostasis, 10.1111/jth.13861, 15:12, (2408-2418), Online publication date: 1-Dec-2017. Xu Z, Xu Y, Hao Y, Ren L, Zhang Z, Xu X, Cao B, Dai K, Zhu L, Fang Q, Kong Y and Mao X (2017) A novel STAT3 inhibitor negatively modulates platelet activation and aggregation, Acta Pharmacologica Sinica, 10.1038/aps.2016.155, 38:5, (651-659), Online publication date: 1-May-2017. Kehrel B and Fender A (2016) Resolving Thromboinflammation in the Brain After Ischemic Stroke?, Circulation, 133:22, (2128-2131), Online publication date: 31-May-2016. Soslau G, Mason C, Lynch S, Benjamin J, Ashak D, Prakash J, Moore A, Bagsiyao P, Albert T, Mathew L and Jost M (2017) Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin, Thrombosis and Haemostasis, 10.1160/TH13-03-0248, 111:01, (140-153), . Tissot J, Canellini G, Rubin O, Angelillo-Scherrer A, Delobel J, Prudent M and Lion N (2013) Blood microvesicles: From proteomics to physiology, Translational Proteomics, 10.1016/j.trprot.2013.04.004, 1:1, (38-52), . January 29, 2013Vol 127, Issue 4 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.112.155366PMID: 23266858 Originally publishedDecember 24, 2012 Keywordsplateletstranscription factorsinflammationthrombosisEditorialsPDF download Advertisement SubjectsPlatelets