Herpesviral G Protein-Coupled Receptors Activate NFAT to Induce Tumor Formation via Inhibiting the SERCA Calcium ATPase

English version České info

G protein-coupled receptors (GPCRs) constitute the largest family of proteins that transmit signal across plasma membrane. Herpesviral GPCRs (vGPCRs) activate diverse signaling cascades and are implicated in viral pathogenesis (e.g., tumor development). In contrast to cellular GPCRs that are chiefly regulated via cognate ligand-association, vGPCRs are constitutively active independent of ligand-binding. vGPCRs provide useful tools to dissect signal transduction from plasma membrane receptors to nuclear transcription factors. To probe the activation of nuclear factor of T cells (NFAT), we demonstrate that vGPCRs target the ER calcium ATPase to increase cytosolic calcium concentration and activate NFAT. Inhibition of NFAT activation impairs tumor formation induced by vGPCRs, implying the antitumor therapeutic potential via disabling NFAT activation.

Vyšlo v časopise: Herpesviral G Protein-Coupled Receptors Activate NFAT to Induce Tumor Formation via Inhibiting the SERCA Calcium ATPase. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004768
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004768

Souhrn

Zdroje

1. Ann Arvin GC-F, Edward Mocarski, Patrick S. Moore, Bernard Roizman, Richard Whitley, and Koichi Yamanishi (2007) Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge Univ Press.

2. Mesri EA, Feitelson MA, Munger K (2014) Human Viral Oncogenesis: A Cancer Hallmarks Analysis. Cell Host Microbe 15: 266–282. doi: 10.1016/j.chom.2014.02.011 24629334

3. Mesri EA, Cesarman E, Boshoff C (2010) Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer 10: 707–719. doi: 10.1038/nrc2888 20865011

4. Thompson MP, Kurzrock R (2004) Epstein-Barr virus and cancer. Clin Cancer Res 10: 803–821. 14871955

5. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332: 1186–1191. 7700311

6. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865–1869. 7997879

7. Vischer HF, Siderius M, Leurs R, Smit MJ (2014) Herpesvirus-encoded GPCRs: neglected players in inflammatory and proliferative diseases? Nat Rev Drug Discov 13: 123–139. doi: 10.1038/nrd4189 24445563

8. Sodhi A, Montaner S, Gutkind JS (2004) Viral hijacking of G-protein-coupled-receptor signalling networks. Nat Rev Mol Cell Biol 5: 998–1012. 15573137

9. Couty JP, Gershengorn MC (2005) G-protein-coupled receptors encoded by human herpesviruses. Trends Pharmacol Sci 26: 405–411. 15990176

10. Slinger E, Langemeijer E, Siderius M, Vischer HF, Smit MJ (2010) Herpesvirus-encoded GPCRs rewire cellular signaling. Mol Cell Endocrinol 331: 179–184. doi: 10.1016/j.mce.2010.04.007 20398729

11. Dorsam RT, Gutkind JS (2007) G-protein-coupled receptors and cancer. Nat Rev Cancer 7: 79–94. 17251915

12. Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC, Cesarman E (1997) Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385: 347–350. 9002520

13. Sodhi A, Chaisuparat R, Hu J, Ramsdell AK, Manning BD, et al. (2006) The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 10: 133–143. 16904612

14. Martin D, Galisteo R, Molinolo AA, Wetzker R, Hirsch E, et al. (2011) PI3Kgamma mediates kaposi's sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis. Cancer Cell 19: 805–813. doi: 10.1016/j.ccr.2011.05.005 21665152

15. Cannon M, Philpott NJ, Cesarman E (2003) The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells. J Virol 77: 57–67. 12477810

16. Pati S, Foulke JS Jr., Barabitskaya O, Kim J, Nair BC, et al. (2003) Human herpesvirus 8-encoded vGPCR activates nuclear factor of activated T cells and collaborates with human immunodeficiency virus type 1 Tat. J Virol 77: 5759–5773. 12719569

17. Montaner S, Sodhi A, Molinolo A, Bugge TH, Sawai ET, et al. (2003) Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3: 23–36. 12559173

18. Ho HH, Ganeshalingam N, Rosenhouse-Dantsker A, Osman R, Gershengorn MC (2001) Charged residues at the intracellular boundary of transmembrane helices 2 and 3 independently affect constitutive activity of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. J Biol Chem 276: 1376–1382. 11031271

19. Lopez-Rodriguez C, Aramburu J, Rakeman AS, Rao A (1999) NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun. Proc Natl Acad Sci U S A 96: 7214–7219. 10377394

20. Miyakawa H, Woo SK, Dahl SC, Handler JS, Kwon HM (1999) Tonicity-responsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity. Proc Natl Acad Sci U S A 96: 2538–2542. 10051678

21. Hogan PG, Chen L, Nardone J, Rao A (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17: 2205–2232. 12975316

22. Muller MR, Rao A (2010) NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol 10: 645–656. doi: 10.1038/nri2818 20725108

23. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, et al. (2006) NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441: 595–600. 16554754

24. Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR (1997) Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 275: 1930–1934. 9072970

25. Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, et al. (2006) A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441: 646–650. 16511445

26. Zhu J, Shibasaki F, Price R, Guillemot JC, Yano T, et al. (1998) Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. Cell 93: 851–861. 9630228

27. Okamura H, Aramburu J, Garcia-Rodriguez C, Viola JP, Raghavan A, et al. (2000) Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity. Mol Cell 6: 539–550. 11030334

28. Ahmad SA, Liu W, Jung YD, Fan F, Wilson M, et al. (2001) The effects of angiopoietin-1 and -2 on tumor growth and angiogenesis in human colon cancer. Cancer Res 61: 1255–1259. 11245414

29. Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, et al. (2001) Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res 61: 2145–2153. 11280779

30. Flockhart RJ, Diffey BL, Farr PM, Lloyd J, Reynolds NJ (2008) NFAT regulates induction of COX-2 and apoptosis of keratinocytes in response to ultraviolet radiation exposure. FASEB J 22: 4218–4227. doi: 10.1096/fj.08-113076 18708588

31. Iniguez MA, Martinez-Martinez S, Punzon C, Redondo JM, Fresno M (2000) An essential role of the nuclear factor of activated T cells in the regulation of the expression of the cyclooxygenase-2 gene in human T lymphocytes. J Biol Chem 275: 23627–23635. 10816557

32. Holmes K, Chapman E, See V, Cross MJ (2010) VEGF stimulates RCAN1.4 expression in endothelial cells via a pathway requiring Ca2+/calcineurin and protein kinase C-delta. PLoS One 5: e11435. doi: 10.1371/journal.pone.0011435 20625401

33. Yu Y, De Waele C, Chadee K (2001) Calcium-dependent interleukin-8 gene expression in T84 human colonic epithelial cells. Inflamm Res 50: 220–226. 11392610

34. Maldonado-Perez D, Brown P, Morgan K, Millar RP, Thompson EA, et al. (2009) Prokineticin 1 modulates IL-8 expression via the calcineurin/NFAT signaling pathway. Biochim Biophys Acta 1793: 1315–1324. doi: 10.1016/j.bbamcr.2009.03.008 19348862

35. Kranias EG, Hajjar RJ (2012) Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome. Circ Res 110: 1646–1660. doi: 10.1161/CIRCRESAHA.111.259754 22679139

36. Vischer HF, Leurs R, Smit MJ (2006) HCMV-encoded G-protein-coupled receptors as constitutively active modulators of cellular signaling networks. Trends Pharmacol Sci 27: 56–63. 16352349

37. Feng H, Sun Z, Farzan MR, Feng P (2010) Sulfotyrosines of the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor promote tumorigenesis through autocrine activation. J Virol 84: 3351–3361. doi: 10.1128/JVI.01939-09 20106924

38. Feng H, Dong X, Negaard A, Feng P (2008) Kaposi's sarcoma-associated herpesvirus K7 induces viral G protein-coupled receptor degradation and reduces its tumorigenicity. PLoS Pathog 4: e1000157. doi: 10.1371/journal.ppat.1000157 18802460

39. Fang WB, Jokar I, Zou A, Lambert D, Dendukuri P, et al. (2012) CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem 287: 36593–36608. doi: 10.1074/jbc.M112.365999 22927430

40. Heissig B, Werb Z, Rafii S, Hattori K (2003) Role of c-kit/Kit ligand signaling in regulating vasculogenesis. Thromb Haemost 90: 570–576. 14515175

41. Ahuja SK, Ozcelik T, Milatovitch A, Francke U, Murphy PM (1992) Molecular evolution of the human interleukin-8 receptor gene cluster. Nat Genet 2: 31–36. 1303245

42. Teicher BA, Fricker SP (2010) CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 16: 2927–2931. doi: 10.1158/1078-0432.CCR-09-2329 20484021

43. Burke JE, Dennis EA (2009) Phospholipase A2 structure/function, mechanism, and signaling. J Lipid Res 50 Suppl: S237–242. doi: 10.1194/jlr.R800033-JLR200 19011112

44. Donato R (1999) Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type. Biochim Biophys Acta 1450: 191–231. 10395934

45. Decker EL, Nehmann N, Kampen E, Eibel H, Zipfel PF, et al. (2003) Early growth response proteins (EGR) and nuclear factors of activated T cells (NFAT) form heterodimers and regulate proinflammatory cytokine gene expression. Nucleic Acids Res 31: 911–921. 12560487

46. Minami T, Jiang S, Schadler K, Suehiro J, Osawa T, et al. (2013) The calcineurin-NFAT-angiopoietin-2 signaling axis in lung endothelium is critical for the establishment of lung metastases. Cell Rep 4: 709–723. doi: 10.1016/j.celrep.2013.07.021 23954784

47. Bala K, Bosco R, Gramolelli S, Haas DA, Kati S, et al. (2012) Kaposi's sarcoma herpesvirus K15 protein contributes to virus-induced angiogenesis by recruiting PLCgamma1 and activating NFAT1-dependent RCAN1 expression. PLoS Pathog 8: e1002927. doi: 10.1371/journal.ppat.1002927 23028325

48. Weibrecht I, Leuchowius KJ, Clausson CM, Conze T, Jarvius M, et al. (2010) Proximity ligation assays: a recent addition to the proteomics toolbox. Expert Rev Proteomics 7: 401–409. doi: 10.1586/epr.10.10 20536310

49. Brulois KF, Chang H, Lee AS, Ensser A, Wong LY, et al. (2012) Construction and manipulation of a new Kaposi's sarcoma-associated herpesvirus bacterial artificial chromosome clone. J Virol 86: 9708–9720. doi: 10.1128/JVI.01019-12 22740391

50. Katritch V, Cherezov V, Stevens RC (2012) Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol 53: 531–556. doi: 10.1146/annurev-pharmtox-032112-135923 23140243

51. Casarosa P, Bakker RA, Verzijl D, Navis M, Timmerman H, et al. (2001) Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. J Biol Chem 276: 1133–1137. 11050102

52. Montaner S, Kufareva I, Abagyan R, Gutkind JS (2013) Molecular mechanisms deployed by virally encoded G protein-coupled receptors in human diseases. Annu Rev Pharmacol Toxicol 53: 331–354. doi: 10.1146/annurev-pharmtox-010510-100608 23092247

53. Mancini M, Toker A (2009) NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer 9: 810–820. doi: 10.1038/nrc2735 19851316

54. Yiu GK, Toker A (2006) NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J Biol Chem 281: 12210–12217. 16505480

55. Jauliac S, Lopez-Rodriguez C, Shaw LM, Brown LF, Rao A, et al. (2002) The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol 4: 540–544. 12080349

56. Glud SZ, Sorensen AB, Andrulis M, Wang B, Kondo E, et al. (2005) A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus. Blood 106: 3546–3552. 16051745

57. Baksh S, Widlund HR, Frazer-Abel AA, Du J, Fosmire S, et al. (2002) NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol Cell 10: 1071–1081. 12453415

58. Carvalho LD, Teixeira LK, Carrossini N, Caldeira AT, Ansel KM, et al. (2007) The NFAT1 transcription factor is a repressor of cyclin A2 gene expression. Cell Cycle 6: 1789–1795. 17637565

59. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, et al. (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277: 55–60. 9204896

60. Oliner J, Min H, Leal J, Yu D, Rao S, et al. (2004) Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6: 507–516. 15542434

61. Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, et al. (2001) Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 276: 18563–18569. 11278747

62. Gately S, Li WW (2004) Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 31: 2–11. 15726515

63. Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, et al. (2009) The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 30: 377–386. doi: 10.1093/carcin/bgp014 19136477

64. Sharma-Walia N, George Paul A, Patel K, Chandran K, Ahmad W, et al. (2010) NFAT and CREB regulate Kaposi's sarcoma-associated herpesvirus-induced cyclooxygenase 2 (COX-2). J Virol 84: 12733–12753. doi: 10.1128/JVI.01065-10 20943963

65. Brinkmann MM, Pietrek M, Dittrich-Breiholz O, Kracht M, Schulz TF (2007) Modulation of host gene expression by the K15 protein of Kaposi's sarcoma-associated herpesvirus. J Virol 81: 42–58. 17050609

66. Sharma-Walia N, Patel K, Chandran K, Marginean A, Bottero V, et al. (2012) COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma-associated herpes virus oncoprotein-v-FLIP. Oncogenesis 1: e5. doi: 10.1038/oncsis.2012.5 23552603

67. Sharma-Walia N, Paul AG, Bottero V, Sadagopan S, Veettil MV, et al. (2010) Kaposi's sarcoma associated herpes virus (KSHV) induced COX-2: a key factor in latency, inflammation, angiogenesis, cell survival and invasion. PLoS Pathog 6: e1000777. doi: 10.1371/journal.ppat.1000777 20169190

68. Punj V, Matta H, Schamus S, Chaudhary PM (2009) Integrated microarray and multiplex cytokine analyses of Kaposi's Sarcoma Associated Herpesvirus viral FLICE Inhibitory Protein K13 affected genes and cytokines in human blood vascular endothelial cells. BMC Med Genomics 2: 50. doi: 10.1186/1755-8794-2-50 19660139

69. Zhu H, Cong JP, Yu D, Bresnahan WA, Shenk TE (2002) Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication. Proc Natl Acad Sci U S A 99: 3932–3937. 11867761

70. Maussang D, Langemeijer E, Fitzsimons CP, Stigter-van Walsum M, Dijkman R, et al. (2009) The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res 69: 2861–2869. doi: 10.1158/0008-5472.CAN-08-2487 19318580

71. Paul AG, Sharma-Walia N, Chandran B (2011) Targeting KSHV/HHV-8 latency with COX-2 selective inhibitor nimesulide: a potential chemotherapeutic modality for primary effusion lymphoma. PLoS One 6: e24379. doi: 10.1371/journal.pone.0024379 21980345

72. Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, et al. (2009) Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459: 1126–1130. doi: 10.1038/nature08062 19458618

73. Ryeom S, Baek KH, Rioth MJ, Lynch RC, Zaslavsky A, et al. (2008) Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. Cancer Cell 13: 420–431. doi: 10.1016/j.ccr.2008.02.018 18455125

74. Dong X, Feng H, Sun Q, Li H, Wu TT, et al. (2010) Murine gamma-herpesvirus 68 hijacks MAVS and IKKbeta to initiate lytic replication. PLoS Pathog 6: e1001001. doi: 10.1371/journal.ppat.1001001 20686657

75. Dong X, Feng P (2011) Murine gamma herpesvirus 68 hijacks MAVS and IKKbeta to abrogate NFkappaB activation and antiviral cytokine production. PLoS Pathog 7: e1002336. doi: 10.1371/journal.ppat.1002336 22110409

76. Wang Y, Lu X, Zhu L, Shen Y, Chengedza S, et al. (2013) IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis. Proc Natl Acad Sci U S A 110: 11139–11144. doi: 10.1073/pnas.1219829110 23771900

77. Gjyshi O, Bottero V, Veettil MV, Dutta S, Singh VV, et al. (2014) Kaposi's sarcoma-associated herpesvirus induces Nrf2 during de novo infection of endothelial cells to create a microenvironment conducive to infection. PLoS Pathog 10: e1004460. doi: 10.1371/journal.ppat.1004460 25340789

78. Bandyopadhyay C, Veettil MV, Dutta S, Chandran B (2014) p130Cas Scaffolds the Signalosome To Direct Adaptor-Effector Cross Talk during Kaposi's Sarcoma-Associated Herpesvirus Trafficking in Human Microvascular Dermal Endothelial Cells. J Virol 88: 13858–13878. doi: 10.1128/JVI.01674-14 25253349