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PpV, acting via the JNK pathway, represses apoptosis during normal development of Drosophila wing

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Abstract

Apoptosis is one of the main fundamental biological processes required for development of multicellular organisms. Inappropriate regulation of apoptosis can lead to severe developmental abnormalities and diseases. Therefore, the control of apoptosis, not only for its activation but also for its inhibition, is critically important during development. In contrast to the extensive studies of apoptosis induction, its inhibitory mechanisms that are even more vital in certain populations of cells actually are very far from being well understood. Here we report an inhibitory role of protein phosphatase V (PpV), a serine/threonine protein phosphatase, in controlling the apoptosis during Drosophila wing development. We observed that inhibition of ppv by RNAi in wing imaginal discs induced ectopic cell death and caspase activation, thus, resulted in a defective adult wing. Moreover, knocking-down ppv triggered the activation of c-Jun N-terminal kinase (JNK) signal, an evolutionarily conserved intracellular signaling that has been implicated to modulate the apoptotic machinery in many biological and experimental systems. Disrupting the JNK signal transduction was adequate to suppress the ppv effects for wing development. Together, we provided the evidence to demonstrate that ppv is required for normal wing development in maintaining the silence of apoptotic signal possibly through JNK pathway.

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References

  1. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516. https://doi.org/10.1080/01926230701320337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jacobson MD, Weil M, Raff MC (1997) Programmed cell death in animal development. Cell 88(3):347–354

    Article  CAS  PubMed  Google Scholar 

  3. Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell 147(4):742–758. https://doi.org/10.1016/j.cell.2011.10.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Favaloro B, Allocati N, Graziano V, Di Ilio C, De Laurenzi V (2012) Role of apoptosis in disease. Aging 4(5):330–349. https://doi.org/10.18632/aging.100459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ranger AM, Malynn BA, Korsmeyer SJ (2001) Mouse models of cell death. Nat Genet 28(2):113–118. https://doi.org/10.1038/88815

    Article  CAS  PubMed  Google Scholar 

  6. Martin FA, Perez-Garijo A, Morata G (2009) Apoptosis in Drosophila: compensatory proliferation and undead cells. Int J Dev Biol 53(8–10):1341–1347. https://doi.org/10.1387/ijdb.072447fm

    Article  PubMed  Google Scholar 

  7. Milan M, Campuzano S, Garcia-Bellido A (1997) Developmental parameters of cell death in the wing disc of Drosophila. Proc Natl Acad Sci USA 94(11):5691–5696

    Article  CAS  PubMed  Google Scholar 

  8. Kumar S (2007) Caspase function in programmed cell death. Cell Death Differ 14(1):32–43. https://doi.org/10.1038/sj.cdd.4402060

    Article  CAS  PubMed  Google Scholar 

  9. Xu D, Woodfield SE, Lee TV, Fan Y, Antonio C, Bergmann A (2009) Genetic control of programmed cell death (apoptosis) in Drosophila. Fly 3(1):78–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Adachi-Yamada T, Fujimura-Kamada K, Nishida Y, Matsumoto K (1999) Distortion of proximodistal information causes JNK-dependent apoptosis in Drosophila wing. Nature 400(6740):166–169. https://doi.org/10.1038/22112

    Article  CAS  PubMed  Google Scholar 

  11. Rios-Barrera LD, Riesgo-Escovar JR (2013) Regulating cell morphogenesis: the Drosophila Jun N-terminal kinase pathway. Genesis 51(3):147–162. https://doi.org/10.1002/dvg.22354

    Article  CAS  PubMed  Google Scholar 

  12. McEwen DG, Peifer M (2005) Puckered, a Drosophila MAPK phosphatase, ensures cell viability by antagonizing JNK-induced apoptosis. Development 132(17):3935–3946. https://doi.org/10.1242/dev.01949

    Article  CAS  PubMed  Google Scholar 

  13. Cohen P (2000) The regulation of protein function by multisite phosphorylation—a 25 year update. Trends Biochem Sci 25(12):596–601

    Article  CAS  PubMed  Google Scholar 

  14. Brautigan DL (2013) Protein Ser/Thr phosphatases—the ugly ducklings of cell signalling. FEBS J 280(2):324–345. https://doi.org/10.1111/j.1742-4658.2012.08609.x

    Article  CAS  PubMed  Google Scholar 

  15. Boe R, Gjertsen BT, Vintermyr OK, Houge G, Lanotte M, Doskeland SO (1991) The protein phosphatase inhibitor okadaic acid induces morphological changes typical of apoptosis in mammalian cells. Exp Cell Res 195(1):237–246

    Article  CAS  PubMed  Google Scholar 

  16. MacKeigan JP, Murphy LO, Blenis J (2005) Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nat Cell Biol 7(6):591–600. https://doi.org/10.1038/ncb1258

    Article  CAS  PubMed  Google Scholar 

  17. Li X, Scuderi A, Letsou A, Virshup DM (2002) B56-associated protein phosphatase 2A is required for survival and protects from apoptosis in Drosophila melanogaster. Mol Cell Biol 22(11):3674–3684. https://doi.org/10.1128/mcb.22.11.3674-3684.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Silverstein AM, Barrow CA, Davis AJ, Mumby MC (2002) Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits. Proc Natl Acad Sci USA 99(7):4221–4226. https://doi.org/10.1073/pnas.072071699

    Article  CAS  PubMed  Google Scholar 

  19. Andrabi S, Gjoerup OV, Kean JA, Roberts TM, Schaffhausen B (2007) Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner. Proc Natl Acad Sci USA 104(48):19011–19016. https://doi.org/10.1073/pnas.0706696104

    Article  PubMed  Google Scholar 

  20. Huang J, Xue L (2015) Loss of flfl Triggers JNK-dependent cell death in Drosophila. Biomed Res Int 2015:623573. https://doi.org/10.1155/2015/623573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mourtada-Maarabouni M, Williams GT (2009) Protein phosphatase 4 regulates apoptosis in leukemic and primary human T-cells. Leuk Res 33(11):1539–1551. https://doi.org/10.1016/j.leukres.2009.05.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Garcia A, Cayla X, Guergnon J, Dessauge F, Hospital V, Rebollo MP, Fleischer A, Rebollo A (2003) Serine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis. Biochimie 85(8):721–726. https://doi.org/10.1016/j.biochi.2003.09.004

    Article  CAS  PubMed  Google Scholar 

  23. Cohen PTW, Brewis ND, Hughes V, Mann DJ (1990) Protein serine/threonine phosphatases; an expanding family. FEBS 268:355–359

    Article  CAS  Google Scholar 

  24. Morrison DK, Murakami MS, Cleghon V (2000) Protein kinases and phosphatases in the Drosophila genome. J Cell Biol 150(2):F57–F62

    Article  CAS  PubMed  Google Scholar 

  25. Afshar K, Werner ME, Tse YC, Glotzer M, Gonczy P (2010) Regulation of cortical contractility and spindle positioning by the protein phosphatase 6 PPH-6 in one-cell stage C. elegans embryos. Development 137(2):237–247. https://doi.org/10.1242/dev.042754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hayashi K, Momoi Y, Tanuma N, Kishimoto A, Ogoh H, Kato H, Suzuki M, Sakamoto Y, Inoue Y, Nomura M, Kiyonari H, Sakayori M, Fukamachi K, Kakugawa Y, Yamashita Y, Ito S, Sato I, Suzuki A, Nishio M, Suganuma M, Watanabe T, Shima H (2015) Abrogation of protein phosphatase 6 promotes skin carcinogenesis induced by DMBA. Oncogene 34(35):4647–4655. https://doi.org/10.1038/onc.2014.398

    Article  CAS  PubMed  Google Scholar 

  27. Kato H, Kurosawa K, Inoue Y, Tanuma N, Momoi Y, Hayashi K, Ogoh H, Nomura M, Sakayori M, Kakugawa Y, Yamashita Y, Miura K, Maemondo M, Katakura R, Ito S, Sato M, Sato I, Chiba N, Watanabe T, Shima H (2015) Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis. Cancer Lett 365(2):223–228. https://doi.org/10.1016/j.canlet.2015.05.022

    Article  CAS  PubMed  Google Scholar 

  28. Ogoh H, Tanuma N, Matsui Y, Hayakawa N, Inagaki A, Sumiyoshi M, Momoi Y, Kishimoto A, Suzuki M, Sasaki N, Ohuchi T, Nomura M, Teruya Y, Yasuda K, Watanabe T, Shima H (2016) The protein phosphatase 6 catalytic subunit (Ppp6c) is indispensable for proper post-implantation embryogenesis. Mech Dev 139:1–9. https://doi.org/10.1016/j.mod.2016.02.001

    Article  CAS  PubMed  Google Scholar 

  29. Wengrod J, Wang D, Weiss S, Zhong H, Osman I, Gardner LB (2015) Phosphorylation of eIF2alpha triggered by mTORC1 inhibition and PP6C activation is required for autophagy and is aberrant in PP6C-mutated melanoma. Sci Signal 8(367):ra27. https://doi.org/10.1126/scisignal.aaa0899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kajihara R, Sakamoto H, Tanabe K, Takemoto K, Tasaki M, Ando Y, Inui S (2014) Protein phosphatase 6 controls BCR-induced apoptosis of WEHI-231 cells by regulating ubiquitination of Bcl-xL. J Immunol 192(12):5720–5729. https://doi.org/10.4049/jimmunol.1302643

    Article  CAS  PubMed  Google Scholar 

  31. Su Y, Ospina JK, Zhang J, Michelson AP, Schoen AM, Zhu AJ (2011) Sequential phosphorylation of smoothened transduces graded hedgehog signaling. Sci Signal 4(180):ra43. https://doi.org/10.1126/scisignal.2001747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Friedman AA, Tucker G, Singh R, Yan D, Vinayagam A, Hu Y, Binari R, Hong P, Sun X, Porto M, Pacifico S, Murali T, Finley RL Jr, Asara JM, Berger B, Perrimon N (2011) Proteomic and functional genomic landscape of receptor tyrosine kinase and ras to extracellular signal-regulated kinase signaling. Sci Signal 4(196):rs10. https://doi.org/10.1126/scisignal.2002029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ma X, Lu JY, Dong Y, Li D, Malagon JN, Xu T (2017) PP6 disruption synergizes with oncogenic ras to promote JNK-dependent tumor growth and invasion. Cell Rep 19(13):2657–2664. https://doi.org/10.1016/j.celrep.2017.05.092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Duffy JB (2002) GAL4 system in Drosophila: a fly geneticist’s Swiss army knife. Genesis 34(1–2):1–15. https://doi.org/10.1002/gene.10150

    Article  CAS  PubMed  Google Scholar 

  35. DeVorkin L, Go NE, Hou YC, Moradian A, Morin GB, Gorski SM (2014) The Drosophila effector caspase Dcp-1 regulates mitochondrial dynamics and autophagic flux via SesB. J Cell Biol 205(4):477–492. https://doi.org/10.1083/jcb.201303144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dhanasekaran DN, Reddy EP (2017) JNK-signaling: a multiplexing hub in programmed cell death. Genes Cancer 8(9–10):682–694. https://doi.org/10.18632/genesandcancer.155

    Article  PubMed  PubMed Central  Google Scholar 

  37. Umemori M, Habara O, Iwata T, Maeda K, Nishinoue K, Okabe A, Takemura M, Takahashi K, Saigo K, Ueda R, Adachi-Yamada T (2009) RNAi-mediated knockdown showing impaired cell survival in Drosophila wing imaginal disc. Gene Regul Syst Biol 3:11–20

    Google Scholar 

  38. Kajino T, Ren H, Iemura S, Natsume T, Stefansson B, Brautigan DL, Matsumoto K, Ninomiya-Tsuji J (2006) Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway. J Biol Chem 281(52):39891–39896. https://doi.org/10.1074/jbc.M608155200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Igaki T, Kanda H, Yamamoto-Goto Y, Kanuka H, Kuranaga E, Aigaki T, Miura M (2002) Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. EMBO J 21(12):3009–3018. https://doi.org/10.1093/emboj/cdf306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Igaki T, Miura M (2014) The Drosophila TNF ortholog Eiger: emerging physiological roles and evolution of the TNF system. Semin Immunol 26(3):267–274. https://doi.org/10.1016/j.smim.2014.05.003

    Article  CAS  PubMed  Google Scholar 

  41. Stronach B, Lennox AL, Garlena RA (2014) Domain specificity of MAP3K family members, MLK and Tak1, for JNK signaling in Drosophila. Genetics 197(2):497–513. https://doi.org/10.1534/genetics.113.160937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yin D, Huang P, Wu J, Song H (2014) Drosophila protein phosphatase V regulates lipid homeostasis via the AMPK pathway. J Mol Cell Biol 6(1):100–102. https://doi.org/10.1093/jmcb/mjt050

    Article  PubMed  Google Scholar 

  43. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L (2012) A landscape of driver mutations in melanoma. Cell 150(2):251–263. https://doi.org/10.1016/j.cell.2012.06.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Sznol M, Kluger HM, Brash DE, Stern DF, Materin MA, Lo RS, Mane S, Ma S, Kidd KK, Hayward NK, Lifton RP, Schlessinger J, Boggon TJ, Halaban R (2012) Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44(9):1006–1014. https://doi.org/10.1038/ng.2359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zeng K, Bastos RN, Barr FA, Gruneberg U (2010) Protein phosphatase 6 regulates mitotic spindle formation by controlling the T-loop phosphorylation state of Aurora A bound to its activator TPX2. J Cell Biol 191(7):1315–1332. https://doi.org/10.1083/jcb.201008106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Du J, Zhang J, He T, Li Y, Su Y, Tie F, Liu M, Harte PJ, Zhu AJ (2016) Stuxnet facilitates the degradation of polycomb protein during development. Dev Cell 37(6):507–519. https://doi.org/10.1016/j.devcel.2016.05.013

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Bloomington Drosophila Stock Center, the Fly Stocks of National Institute of Genetics, the Vienna Drosophila RNAi Center, and the Tsinghua Stock Center, Shanghai Core Facility of Drosophila Resource and Technology CAS for fly stocks. This work was supported by the Fundamental Research Funds for the Central Universities (201612010 to Y. Su, 201762003 and 201562029), National Natural Science Foundation of China (31701274 to Y. Su), and China Postdoctoral Science Foundation (2017M612349 to Y. Su).

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Correspondence to Long Zhao or Ying Su.

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Chi, C., Wang, L., Lan, W. et al. PpV, acting via the JNK pathway, represses apoptosis during normal development of Drosophila wing. Apoptosis 23, 554–562 (2018). https://doi.org/10.1007/s10495-018-1479-2

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