Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Ahmad R. SafaEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101547


Integration of the Mitochondrial and Death Receptors (DRs) Pathways and Role of c-FLIP

Two major signaling pathways, the intrinsic or mitochondrial pathway and the extrinsic or cell surface DRs pathway, regulate apoptosis (Fig. 1) (Lavrik et al. 2005; Micheau and Tschopp 2003; Safa et al. 2008). In the intrinsic pathway, various anti- and pro-apoptotic members of the Bcl-2 family form an interactive network that finally regulates the release of apoptosis-triggering factors such as cytochrome c, apoptosis-inducing factors including Smac/DIABLO, HtrA2/Omi, and Endonuclease G (endoG) from the mitochondria to the cytosol (Vaux 2011; Plati et al. 2011). Upon release, cytochrome cand dATP bind to apoptotic proteinase-activating factor-1 (Apaf-1), and this complex along with adenine nucleotides forms the apoptosome and promotes procaspase-9...
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I would like to thank Dr. Mary D. Kraeszig for her editorial assistance. The work in the author’s laboratory was supported by research grants from the National Cancer Institute (CA 080734, CA 90878, and CA 101743), Department of Defense (DOD) (OC 06095), and the Indiana University Cancer Center Translational Research Acceleration Collaboration (ITRAC) initiative.


  1. Bagnoli M, Canevari S, Mezzanzanica D. Cellular FLICE-inhibitory protein (c-FLIP) signalling: a key regulator of receptor-mediated apoptosis in physiologic context and in cancer. Int J Biochem Cell Biol. 2010;42:210–3.  https://doi.org/10.1016/j.biocel.2009.11.015.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Cain K, Bratton SB, Langlais C, Walker G, Brown DG, Sun XM, Cohen GM. Apaf-1 oligomerizes into biologically active approximately 700-kDa and inactive approximately 1.4-MDa apoptosome complexes. J Biol Chem. 2000;275:6067–70.PubMedCrossRefGoogle Scholar
  3. Chang DW1, Xing Z, Pan Y, Algeciras-Schimnich A, Barnhart Bc, Yaish-Ohad S. et al. c-FLIOL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J. 2002;21:3704–14.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Cao X, Pobezinskaya YL, Morgan MJ, Liu ZG. The role of TRADD in TRAIL-induced apoptosis and signaling. FASEB J. 2011;4:1353–8.  https://doi.org/10.1096/fj.10-170480.CrossRefGoogle Scholar
  5. Day TW, Najafi F, Wu CH, Safa AR. Cellular FLICE-like inhibitory protein (c-FLIP): a novel target for Taxol-induced apoptosis. Biochem Pharmacol. 2006;71:1551–61.PubMedCrossRefGoogle Scholar
  6. Du X, Bao G, He X, Zhao H, Yu F, Qiao Q, et al. Expression and biological significance of c-FLIP in human hepatocellular carcinomas. J Exp Clin Cancer Res. 2009;28:24.  https://doi.org/10.1186/1756-9966-28-24.CrossRefPubMedPubMedCentralGoogle Scholar
  7. El-Gazzar A, Wittinger M, Perco P, Anees M, Horvat R, Mikulits W, et al. The role of c-FLIP(L) in ovarian cancer: chaperoning tumor cells from immunosurveillance and increasing their invasive potential. Gynecol Oncol. 2010;117:451–9.  https://doi.org/10.1016/j.ygyno.2010.02.024.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Ewald F, Annemann M, Pils MC, Plaza-Sirvent C, Neff F, Erck C, Reinhold D, Schmitz I. Constitutive expression of murine c-FLIPR causes autoimmunity in aged mice. Cell Death Dis. 2014;5:e1168.  https://doi.org/10.1038/cddis.2014.138.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, et al. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell. 2011;43:449–63.  https://doi.org/10.1016/j.molcel.2011.06.011.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Gilot D, Serandour AL, Ilyin GP, Lagadic-Gossmann D, Loyer P, Corlu A, et al. A role for caspase-8 and c-FLIPL in proliferation and cell-cycle progression of primary hepatocytes. Carcinogenesis. 2005;26:2086–94.PubMedCrossRefGoogle Scholar
  11. Golan-Gerstl R, Wallach-Dayan SB, Zisman P, Cardoso WV, Goldstein RH, Breuer R. Cellular FLICE-like inhibitory protein deviates myofibroblast Fas-induced apoptosis toward proliferation during lung fibrosis. Am J Respir Cell Mol Biol. 2012;47:271–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Golks A, Brenner D, Fritsch C, Krammer PH, Lavrik IN. c-FLIPR, a new regulator of death receptor-induced apoptosis. J Biol Chem. 2005;280:14507–13.PubMedCrossRefGoogle Scholar
  13. Golks A, Brenner D, Krammer PH, Lavrik IN. The c-FLIP-NH2 terminus (p22-FLIP) induces NF-κB activation. J Exp Med. 2006;203:1295–305.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Grimm S. The ER-mitochondria interface: the social network of cell death. Biochim Biophys Acta. 2012;1823:327–34.  https://doi.org/10.1016/j.bbamcr.2011.11.018.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Haimerl F, Erhardt A, Sass G, Tiegs G. Down-regulation of the de-ubiquitinating enzyme ubiquitin-specific protease 2 contributes to tumor necrosis factor-alpha-induced hepatocyte survival. J Biol Chem. 2009;284:495–4.  https://doi.org/10.1074/jbc.M803533200.CrossRefPubMedPubMedCentralGoogle Scholar
  16. He MX, He YW. A role for c-FLIPL in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes. Cell Death Differ. 2013;2:188–97.  https://doi.org/10.1038/cdd.2012.148.CrossRefGoogle Scholar
  17. Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, et al. Inhibition of death receptor signals by cellular FLIP. Nature. 1997;388:190–5.PubMedCrossRefGoogle Scholar
  18. Kang HK, Ecklund D, Liu M, Datta SK. Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells. Arthritis Res Ther. 2009;11:R59.  https://doi.org/10.1186/ar2682.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Kataoka T, Tschopp J. N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway. Mol Cell Biol. 2004;24:2627–36.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Kerr E, Holohan C, McLaughlin KM, Majkut J, Dolan S, Redmond K, et al. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ. 2012;19:1317–27.  https://doi.org/10.1038/cdd.2012.8.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kim MJ, Kim HB, Bae JH, Lee JW, Park SJ, et al. Sensitization of human K562 leukemic cells to TRAIL-induced apoptosis by inhibiting the DNA-PKcs/Akt-mediated cell survival pathway. Biochem Pharmacol. 2009;78:573–82.PubMedCrossRefGoogle Scholar
  22. Korkolopoulou P, Saetta AA, Levidou G, Gigelou F, Lazaris A, Thymara I, et al. c-FLIP expression in colorectal carcinomas: association with Fas/FasL expression and prognostic implications. Histopathology. 2007;51:150–6.  https://doi.org/10.1038/cdd.2012.8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Krammer PH, Kamiński M, Kiessling M, Gülow K. No life without death. Adv Cancer Res. 2007;97:111–38.PubMedCrossRefGoogle Scholar
  24. Lavrik IN, Krammer PH. Regulation of CD95/Fas signaling at the DISC. Cell Death Differ. 2012;19:36–41.PubMedCrossRefGoogle Scholar
  25. Lavrik I, Golks A, Krammer PH. Death receptor signaling. J Cell Sci. 2005;118:265–67.PubMedCrossRefGoogle Scholar
  26. Leverkus M, Diessenbacher P, Geserick P. FLIPing the coin? Death receptor-mediated signals during skin tumorigenesis. Exp Dermatol. 2008;17:614–22.PubMedCrossRefGoogle Scholar
  27. Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell. 1996;86:147–57.PubMedCrossRefGoogle Scholar
  28. Mezache L, Mikhail M, Garofalo M, Nuovo GJ. Reduced miR-512 and the elevated expression of its targets cFLIP and MCL1 localize to neurons with hyperphosphorylated tau protein in Alzheimer disease. Appl Immunohistochem Mol Morphol. 2015;23:615–23.PubMedCrossRefGoogle Scholar
  29. Micheau O. Cellular FLICE-inhibitory protein: an attractive therapeutic target? Expert Opin Ther Targets. 2003;7:559–73.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181–90.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol. 2010;12:823–30.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Naito M, Katayama R, Ishioka T, Takada R, Fujita N, Tsuruo T, et al. Cellular FLIP inhibits β-catenin ubiquitylation and enhances Wnt signaling. Mol Cell Biol. 2004;24:8418–27.  https://doi.org/10.1242/jcs.058602.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Nakajima A, Komazawa-Sakon S, Takekawa M, Sasazuki T, Yeh WC, Yagita H, et al. An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway. EMBO J. 2006;25:5549–59.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Nakajima A, Kojima Y, Nakayama M, Yagita H, Okumura K, Nakano H. Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells. Oncogene. 2008;27:76–84.PubMedCrossRefGoogle Scholar
  35. Oztürk S, Schleich K, Lavrik IN. Cellular FLICE-like inhibitory proteins (c-FLIPs): fine-tuners of life and death decisions. Exp Cell Res. 2012;318:1324–31.  https://doi.org/10.1016/j.yexcr.2012.01.019.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Pallares J, Llobet D, Santacana M, Eritja N, Velasco A, Cuevas D, Lopez S, Palomar-Asenjo V, Yeramian A, Dolcet X. Matias-Guiu X. CK2beta is expressed in endometrial carcinoma and has a role in apoptosis resistance and cell proliferation. Am J Pathol. 2009;174:287–96.  https://doi.org/10.2353/ajpath.2009.080552.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Peter ME. The flip side of FLIP. Biochem J. 2004;382(Pt 2):e1–3.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;2011(3):279–96.CrossRefGoogle Scholar
  39. Quintavalle C, Incoronato M, Puca L, Acunzo M, Zanca C, Romano G, et al. c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3β activity. Cell Death Differ. 2010;17:1908–16.CrossRefGoogle Scholar
  40. Ranjan K, Pathak C. Expression of FADD and cFLIPL balances mitochondrial integrity and redox signaling to substantiate apoptotic cell death. Mol Cell Biochem. 2016a;422:135–50.PubMedCrossRefGoogle Scholar
  41. Ranjan K, Pathak C. Expression of cFLIPL determines the basal interaction of Bcl-2 with Beclin-1 and regulates p53 dependent ubiquitination of Beclin-1 during autophagic stress. J Cell Biochem. 2016b;117:1757–68.  https://doi.org/10.1002/jcb.25474.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Reubold TF, Eschenburg S. A molecular view on signal transduction by the apoptosome. Cell Signal. 2012;24:1420–5.PubMedCrossRefGoogle Scholar
  43. Safa AR. c-FLIP, a master anti-apoptotic regulator. Exp Oncol. 2012;34:176–84.PubMedPubMedCentralGoogle Scholar
  44. Safa AR. Roles of c-FLIP in apoptosis, necroptosis, and autophagy. J Carcinog Mutagen. 2013; Suppl 6. pii: 003.  https://doi.org/10.4172/2157-2518.S6-003.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Safa AR, Pollok KE. Targeting the anti-apoptotic protein c-FLIP for cancer therapy. Cancers (Basel). 2011;3:1639–71.  https://doi.org/10.3390/cancers3021639.CrossRefGoogle Scholar
  46. Safa AR, Day TW, Wu CH. Cellular FLICE-like inhibitory protein (c-FLIP): a novel target for cancer therapy. Curr Cancer Drug Targets. 2008;8:37–46.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 1998;17:1675–87.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Seidelin JB, Coskun M, Vainer B, Riis L, Soendergaard C, Nielsen OH. ERK controls epithelial cell death receptor signalling and cellular FLICE-like inhibitory protein (c-FLIP) in ulcerative colitis. J Mol Med (Berl). 2013;91:839–49.  https://doi.org/10.1007/s00109-013-1003-7. Epub 2013 Feb 1.CrossRefGoogle Scholar
  49. Silke J, Strasser A. The FLIP side of life. Sci Signal. 2013;6:pe2.  https://doi.org/10.1126/scisignal.2003845.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Tao J, Dong J, Li Y, Liu YQ, Yang J, Wu Y, et al. Up-regulation of cellular FLICE-inhibitory protein in peripheral blood B lymphocytes in patients with systemic lupus erythematosus is associated with clinical characteristics. J Eur Acad Dermatol Venereol. 2009;23:433–7.PubMedCrossRefGoogle Scholar
  51. Telieps T, Ewald F, Gereke M, Annemann M, Rauter Y, Schuster M, et al. c-FLIPR modulates cell death induction upon T-cell activation and infection. Eur J Immunol. 2013;43:1499–510.  https://doi.org/10.1002/eji.201242819.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, et al. The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell. 2011;43:432–48.  https://doi.org/10.1016/j.molcel.2011.06.006.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature. 1997;386:517–21.PubMedCrossRefGoogle Scholar
  54. Tian F, Lu JJ, Wang L, Li L, Yang J, Li Y, et al. Expression of c-FLIP in malignant melanoma, and its relationship with the clinicopathological features of the disease. Clin Exp Dermatol. 2012;37:259–65.  https://doi.org/10.1111/j.1365-2230.2011.04238.x.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Trivedi R, Mishra DP. Trailing TRAIL resistance: novel targets for TRAIL sensitization in cancer cells. Front Oncol. 2015;5:69.  https://doi.org/10.3389/fonc.2015.00069.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Vaux DL. Apoptogenic factors released from mitochondria. Biochim Biophys Acta. 2011;13:546–50.  https://doi.org/10.1016/j.bbamcr.2010.08.002.CrossRefGoogle Scholar
  57. Walsh CM, Edinger AL. The complex interplay between autophagy, apoptosis, and necrotic signals promotes T-cell homeostasis. Immunol Rev. 2010;236:95–109.  https://doi.org/10.1111/j.1600-065X.2010.00919.x.CrossRefPubMedPubMedCentralGoogle Scholar
  58. Wang X, Lin Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol Sin. 2008;29:1275–88.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Wang W, Zhou J, Shi J, Zhang Y, Liu S, Liu Y, et al. Human T-cell leukemia virus type 1 Tax-deregulated autophagy pathway and c-FLIP expression contribute to resistance against death receptor-mediated apoptosis. J Virol. 2014;88:2786–98.  https://doi.org/10.1128/JVI.03025-13.PubMedCrossRefGoogle Scholar
  60. Xiao J, Moon M, Yan L, Nian M, Zhang Y, Liu C, et al. Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction. Basic Res Cardiol. 2012;107:239.  https://doi.org/10.1007/s00395-011-0239-z.CrossRefPubMedPubMedCentralGoogle Scholar
  61. Yang A, Wilson NS, Ashkenazi A. Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation. Curr Opin Cell Biol. 2010;22:837–44.  https://doi.org/10.1016/j.ceb.2010.08.001.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Yao Q, Du J, Lin J, Luo Y, Wang Y, Liu Y, et al. Prognostic significance of TRAIL signalling molecules in cervical squamous cell carcinoma. J Clin Pathol. 2016;69:122–7.  https://doi.org/10.1136/jclinpath-2014-202811.CrossRefPubMedPubMedCentralGoogle Scholar
  63. Yeh WC, Itie A, Elia AJ, Ng M, Shu HB, Wakeham A, et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity. 2000;12:633–42.PubMedCrossRefGoogle Scholar
  64. Yu JW, Shi Y. FLIP and the death effector domain family. Oncogene. 2008;27:6216–27.  https://doi.org/10.1038/onc.2008.299.CrossRefPubMedPubMedCentralGoogle Scholar
  65. Yuan S, Topf M, Reubold TF, Eschenburg S, Akey CW. Changes in apaf-1 conformation that drive apoptosome assembly. Biochemistry. 2013;52:2319–27.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Zang F, Wei X, Sun B. Relationship of c-FLIPL protein expression with molecular subtyping and clinical prognosis in invasive breast cancer. Zhonghua Bing Li Xue Za Zhi. 2014;43:442–6.Google Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyIndiana University School of MedicineIndianapolisUSA
  2. 2.Indiana University Simon Cancer CenterIndiana University School of MedicineIndianapolisUSA