Apoptosis and survival - Ceramides signaling pathway

Click on a target from the pathway image to view related information. Zoom     View Legend

photo_map
 


Human PrimePCR Selections
photo_fpc
Apoptosis and survival-Ceramides signaling pathway H96

Predesigned 96-well panel for use with SYBR® Green

 

List Price:  $366.00

 

Your Price : Log In

photo_fpc
Apoptosis and survival-Ceramides signaling pathway H384

Predesigned 384-well panel for use with SYBR® Green

 

List Price:  $366.00

 

Your Price : Log In

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].



References

  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

Target Details

Click on a target from the pathway image to view related information.

[ Close ]
Click here to print
[ Close ]
Click here to print
 

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined