Apoptosis and survival - Ceramides signaling pathway


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Ceramides signaling pathway

Ceramides regulate diverse signaling pathways involving apoptosis, cell senescence, the cell cycle, and differentiation. Preliminary Ceramides effects are antagonistic to growth and survival [1], [2].

Ceramides levels are elevated in response to diverse stress challenges including irradiation, heat and cytokines. For instance, Ceramides act as second messengers in tumor necrosis factor (TNF-alpha)/ Tumor necrosis factor receptor superfamily, member 1 (TNF-R1) signaling [1], [2], [3]. TNF-R1 binds adaptor Neutral sphingomyelinase activation associated factor (FAN) that transducer signal to Neutral sphingomyelinase [4]. TNF-R1 activates Acid sphingomyelinase via pathway, which require TNFRSF1A-associated via death domain (TRADD)/ Fas (TNFRSF6)-associated via death domain (FADD) adaptor proteins [5], [6]. Acid and Neutral sphingomyelinases probably can trigger different TNF-alpha-induced pathways. Ceramide produced by Neutral sphingomyelinase stimulates Ceramides-activated Mitogen-activated protein kinase 1 and 3 (ERK1/2) cascade and Acid sphingomyelinase may couple the TNF-R1 to the secretary pathway and to apoptosis via Cathepsin D [6].

Ceramides induce TNF-alpha/ ERK1/2 cascade via Kinase suppressor of ras 1 (KSR). KSR is a molecular scaffold coordinating the Raf (v-myc myelocytomatosis viral oncogene homolog (c-Raf-1))/ Mitogen-activated protein kinase kinase 1 (MEK1) interaction [7], [8], [9]. Ceramides signaling in some cases was shown to be dependent on v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) [8], [10]. This can be explained by scaffolding properties of KSR [9]. TNF-alpha and Ceramides activation of H-Ras leads to Phosphoinositide-3-kinase (PI3K reg class IA (p85))/ PI3K cat) activation and then to fibroblasts proliferation [10]. And controversially, KSR/ c-Raf-1/ MEK1(MAP2K1) [8]/ ERK1/2 [7] -dependent pathway can lead to inhibition of PI3K/ v-akt murine thymoma viral oncogene homolog (AKT(PKB)) activation. This prevents BCL2-associated agonist of cell death (BAD) phosphorylation and leads to apoptosis in COS-7 cells. The mechanism is not elucidated [7], [8], [11]. Also, Inhibition of AKT(PKB) by Ceramides can be a pathway of Ceramides-induced inhibition of Insulin-induced glucose uptake. Ceramides can suppress AKT(PKB) activity without PI3K inhibition. This inhibition depends on protein phosphatase 2 (PP2A)-mediated dephosphorylation and by blocking AKT(PKB) translocation to plasma membrane via Protein kinase C zeta (PKC-zeta). Ceramides can directly bind and activate PKC-zeta and PP2A. [12], [13], [14], [15].

Ceramides can participate in Fas ligand (FasL(TNFSF6)) signaling leading to apoptosis [16], [17], [18]. FasL(TNFSF6) binds Fas (FasR(CD95)) that induces Caspase-8-mediated Acid sphingomyelinase [19] and Caspase-3-mediated Neutral sphingomyelinase activation [20] and production of Ceramides. Ceramides then promotes Ras-dependent apoptosis [21].

PKC-zeta directly binds and activates Mitogen-activated protein kinase kinase kinase 1 (MEKK1(MAP3K1)), Mitogen-activated protein kinase kinase 4 (MEK4(MAP2K4)), Mitogen-activated protein kinase 8 (JNK1(MAPK8)) [22]. Activation of JNK1(MAPK8) pathway by TNF-alpha and Ceramides leads to apoptosis [23]. Ceramides-induced mitogen-activated protein kinase kinase kinase 7 (TAK1(MAP3K7)) also participates in this process [11], [24].

Ceramides via Cathepsin D/ BH3 interacting domain death agonist (Bid)/ Cytochrome c mediates TNF-alpha induced apoptosis. Mitochondrial pathway of apoptosis includes activation of Caspases-3 and Caspases-9 [25], [26], [27].


  1. Mathias S, Peña LA, Kolesnick RN
    Signal transduction of stress via ceramide. The Biochemical journal 1998 Nov 1;335 ( Pt 3):465-80
  2. Ruvolo PP
    Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 2001 Aug;15(8):1153-60
  3. Yan F, Polk DB
    Kinase suppressor of ras is necessary for tumor necrosis factor alpha activation of extracellular signal-regulated kinase/mitogen-activated protein kinase in intestinal epithelial cells. Cancer research 2001 Feb 1;61(3):963-9
  4. Malagarie-Cazenave S, Ségui B, Lévêque S, Garcia V, Carpentier S, Altié MF, Brouchet A, Gouazé V, Andrieu-Abadie N, Barreira Y, Benoist H, Levade T
    Role of FAN in tumor necrosis factor-alpha and lipopolysaccharide-induced interleukin-6 secretion and lethality in D-galactosamine-sensitized mice. The Journal of biological chemistry 2004 Apr 30;279(18):18648-55
  5. Wiegmann K, Schwandner R, Krut O, Yeh WC, Mak TW, Krönke M
    Requirement of FADD for tumor necrosis factor-induced activation of acid sphingomyelinase. The Journal of biological chemistry 1999 Feb 26;274(9):5267-70
  6. Krönke M
    Involvement of sphingomyelinases in TNF signaling pathways. Chemistry and physics of lipids 1999 Nov;102(1-2):157-66
  7. Zhang Y, Yao B, Delikat S, Bayoumy S, Lin XH, Basu S, McGinley M, Chan-Hui PY, Lichenstein H, Kolesnick R
    Kinase suppressor of Ras is ceramide-activated protein kinase. Cell 1997 Apr 4;89(1):63-72
  8. Basu S, Bayoumy S, Zhang Y, Lozano J, Kolesnick R
    BAD enables ceramide to signal apoptosis via Ras and Raf-1. The Journal of biological chemistry 1998 Nov 13;273(46):30419-26
  9. Roy F, Laberge G, Douziech M, Ferland-McCollough D, Therrien M
    KSR is a scaffold required for activation of the ERK/MAPK module. Genes & development 2002 Feb 15;16(4):427-38
  10. Hanna AN, Chan EY, Xu J, Stone JC, Brindley DN
    A novel pathway for tumor necrosis factor-alpha and ceramide signaling involving sequential activation of tyrosine kinase, p21(ras), and phosphatidylinositol 3-kinase. The Journal of biological chemistry 1999 Apr 30;274(18):12722-9
  11. Basu S, Kolesnick R
    Stress signals for apoptosis: ceramide and c-Jun kinase. Oncogene 1998 Dec 24;17(25):3277-85
  12. Zhou H, Summers SA, Birnbaum MJ, Pittman RN
    Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis. The Journal of biological chemistry 1998 Jun 26;273(26):16568-75
  13. Schubert KM, Scheid MP, Duronio V
    Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473. The Journal of biological chemistry 2000 May 5;275(18):13330-5
  14. Powell DJ, Hajduch E, Kular G, Hundal HS
    Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Molecular and cellular biology 2003 Nov;23(21):7794-808
  15. Stratford S, Hoehn KL, Liu F, Summers SA
    Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. The Journal of biological chemistry 2004 Aug 27;279(35):36608-15
  16. Tepper CG, Jayadev S, Liu B, Bielawska A, Wolff R, Yonehara S, Hannun YA, Seldin MF
    Role for ceramide as an endogenous mediator of Fas-induced cytotoxicity. Proceedings of the National Academy of Sciences of the United States of America 1995 Aug 29;92(18):8443-7
  17. Pru JK, Hendry IR, Davis JS, Rueda BR
    Soluble Fas ligand activates the sphingomyelin pathway and induces apoptosis in luteal steroidogenic cells independently of stress-activated p38(MAPK). Endocrinology 2002 Nov;143(11):4350-7
  18. Gulbins E
    Regulation of death receptor signaling and apoptosis by ceramide. Pharmacological research : the official journal of the Italian Pharmacological Society 2003 May;47(5):393-9
  19. Rotolo JA, Zhang J, Donepudi M, Lee H, Fuks Z, Kolesnick R
    Caspase-dependent and -independent activation of acid sphingomyelinase signaling. The Journal of biological chemistry 2005 Jul 15;280(28):26425-34
  20. Watanabe M, Kitano T, Kondo T, Yabu T, Taguchi Y, Tashima M, Umehara H, Domae N, Uchiyama T, Okazaki T
    Increase of nuclear ceramide through caspase-3-dependent regulation of the "sphingomyelin cycle" in Fas-induced apoptosis. Cancer research 2004 Feb 1;64(3):1000-7
  21. Gulbins E, Bissonnette R, Mahboubi A, Martin S, Nishioka W, Brunner T, Baier G, Baier-Bitterlich G, Byrd C, Lang F
    FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity 1995 Apr;2(4):341-51
  22. Bourbon NA, Yun J, Kester M
    Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex. The Journal of biological chemistry 2000 Nov 10;275(45):35617-23
  23. Verheij M, Bose R, Lin XH, Yao B, Jarvis WD, Grant S, Birrer MJ, Szabo E, Zon LI, Kyriakis JM, Haimovitz-Friedman A, Fuks Z, Kolesnick RN
    Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 1996 Mar 7;380(6569):75-9
  24. Shirakabe K, Yamaguchi K, Shibuya H, Irie K, Matsuda S, Moriguchi T, Gotoh Y, Matsumoto K, Nishida E
    TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. The Journal of biological chemistry 1997 Mar 28;272(13):8141-4
  25. Yoshimura S, Banno Y, Nakashima S, Takenaka K, Sakai H, Nishimura Y, Sakai N, Shimizu S, Eguchi Y, Tsujimoto Y, Nozawa Y
    Ceramide formation leads to caspase-3 activation during hypoxic PC12 cell death. Inhibitory effects of Bcl-2 on ceramide formation and caspase-3 activation. The Journal of biological chemistry 1998 Mar 20;273(12):6921-7
  26. Heinrich M, Wickel M, Winoto-Morbach S, Schneider-Brachert W, Weber T, Brunner J, Saftig P, Peters C, Krönke M, Schütze S
    Ceramide as an activator lipid of cathepsin D. Advances in experimental medicine and biology 2000;477:305-15
  27. Heinrich M, Neumeyer J, Jakob M, Hallas C, Tchikov V, Winoto-Morbach S, Wickel M, Schneider-Brachert W, Trauzold A, Hethke A, Schütze S
    Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell death and differentiation 2004 May;11(5):550-63

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