Caspase-8 regulation of TRAIL-mediated cell death

Crowder R.N.1, El-Deiry W.S.2

Summary. Research on TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors has advanced tremendously over the past 17 years. Initial observations of TRAIL and TRAIL receptor-mediated tumor cell toxicity led to enthusiasm of exploiting this selective, malignant cell killing for cancer therapy. Further examination revealed aberrant TRAIL signaling in some cancer cells leading to protection from TRAIL-mediated cell death. Mechanisms of TRAIL resistance often involve decreased expression or activity of initiator caspase-8, crucial for complete TRAIL signal transduction. Caspase-8 mutations, epigenetic silencing, decrease in stability, and incomplete activation have been reported. This article reviews the discovery of TRAIL and TRAIL receptors and subsequent studies that reveal how expression and function of caspase-8 are central to TRAIL-mediated cell death. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.

Received: June 18, 2012.
*Correspondence: Fax: 717-531-5076
E-mail: wafik.eldeiry@gmail.com
Abbreviations used: 5-Aza-5’ – aza-deoxycytidine; Apaf-1 – apoptosis protease-activating factor-1; Bcl-2 – B-cell lymphoma 2; Bid – Bcl-2 interacting protein; CARP1 – caspase-8 and caspase-10-associated RING protein 1; CARP2 – caspase-8 and caspase-10-associated RING protein 2; CUL3 – cullin 3; DcR1 – decoy receptor 1; DcR2 – decoy receptor 2; DISC – death-inducing signaling complex; DR4 – death receptor 4; DR5 – death receptor 5; FADD – Fas-associated death domain protein; HDAC – histone deacetylase; IFNγ – interferon gamma; OPG – osteoprotegerin; PHA – phytohemagglutinin; RING – really interesting new gene; RIP1 – receptor-interacting protein 1; SAHA – suberoylanilide hydroxamic acid; tBid – truncated Bid; TRAIL – TNF-related apoptosis inducing ligand; VA – valproic acid.

Introduction

The discovery of TNF-related apoptosis-inducing ligand (TRAIL) in 1995 was the beginning of exciting research that is now approaching two decades [1]. TRAIL was identified as a member of the TNF family [2]. By 1998, five TRAIL receptors had been discovered and characterized. TRAIL-receptor 1 (DR4) and TRAIL-receptor 2 (DR5) are pro-apoptotic TRAIL receptors capable of mediating cell death. TRAIL-receptor 3 (DcR1) and TRAIL-receptor 4 (DcR2) are decoy TRAIL receptors unable to induce cell death due to deficient intracellular signaling domain or truncated death domain, respectively [3–7]. Osteoprotegerin (OPG), identified in 1998, is a soluble TRAIL decoy receptor shown to be important for osteoclast development [8].

TRAIL expression has been found in various types of human tissues. Endogenous TRAIL has both innate and adaptive immune system functions [9]. TRAIL plays a role in immunosurveillance and has been shown to kill malignant cells as wells as bacterial and viral infected cells [9]. TRAIL’s ability to cause toxicity in various cancer cells while leaving normal cells unharmed made it an exciting, potential cancer therapy. TRAIL-based therapies are currently being evaluated for clinical use.

Cancer cell resistance to TRAIL-mediated cell death has been noted and resistance mechanisms have been investigated extensively. Mechanisms include but are not limited to aberrant TRAIL receptor cell surface expression and presentation [10], TRAIL receptor glycosylation [11], recruitment of the functionally inactive caspase-8 homologue FLIP to the death-inducing signaling complex (DISC) [12, 13], decreased oncogene c-myc expression [14], and increased anti-apoptotic Bcl-2 family member Mcl-1 expression [15]. These mechanisms are of importance and have provided insight into molecular determinants of TRAIL sensitivity. However, this review will focus on caspase regulation of TRAIL-induced cell death, specifically caspase-8. Initiator caspase-10 can be recruited to the DISC but cannot functionally substitute for caspase-8 in mediating cell death [16, 17]. Caspase-8 is the focal apical caspase for the TRAIL signaling pathway and this review will highlight the significance of caspase-8 expression and activity in TRAIL-induced apoptosis [18].

Caspase-8

Caspase-8 is a 55 kDA cysteine protease. Caspase-8 has 480 amino acids and contains two death effector domains and a catalytic protease domain [18]. Procaspase-8 is the inactive zymogen that requires activation for complete activity [18]. Caspase-8 requires multiple steps for activation that include oligomerization and proteolysis cleavage [19]. Active caspase-8 consists of a tetramer with two large and small subunits. The first cleavage of caspase-8 generates p43/41 intermediate fragments. Additional cleavage product are p26/24, p18 and p10 fragments [19]. Multiple caspase-8 isoforms have been described with caspase-8/a (55 kDa) and caspase-8/b (53 kDa) being the predominant isoforms expressed in cells and the characteristic caspase-8 doublet seen by western blotting [20]. A caspase-8 alternative splice variant, caspase-8L, has been identified and can protect against caspase-8-mediated cell death [21, 22].

TRAIL signaling

TRAIL signaling leads to cell death by utilizing both extrinsic and intrinsic pathways [19, 23]. The intrinsic pathway involves mitochondrial permeabilization and release of pro-apoptotic factors that lead to caspase cascade activation. TRAIL ligation to DR4 or DR5 causes receptor clustering and trimerization. Intracellular adaptor protein FADD is recruited to the death domain of the TRAIL receptor. Initiator caspase-8 is recruited to the complex collectively known as the death-inducing signaling complex (DISC) and interacts with FADD through their death effector domains [24]. DISC activation of caspase-8 leads to caspase cascade activation where downstream effector caspase-3 becomes activated and cleaves protein targets that culminate in cell death. Additionally, caspase-8 can cleave the Bcl-2 related protein Bid. Truncated Bid (tBid) translocates into the mitochondria and causes release of cytochrome c and the formation of the Apaf-1containing apoptosome and subsequent caspase-9 activation [24]. Activated caspase-9 can then activate effector caspase-3 resulting in cell death (Fig. 1).

 Caspase 8 regulation of TRAIL mediated cell death
Fig. 1. Extrinsic and intrinsic TRAIL signaling pathways. TRAIL ligation to a pro-apoptotic TRAIL receptor causes receptor trimerization and activation of initiator caspase-8 and effector caspase-3, leading to cell death. Alternatively, caspase-8 can cleave Bid. Truncated Bid triggers the release of cytochrome c and formation of the apoptosome. The apoptosome activates caspase-9 resulting in activation of caspase-3 and cell death

TRAIL resistance

Caspase-8 mutations

Caspase-8 mutations in malignant cells were first noted in squamous cell carcinoma of the oral cavi­ty. A point mutation that altered the stop codon and increased the size of the encoded protein was found in patient-derived cells but not in autologous PHA-treated blood lymphocytes [25]. These cancer cells were also less sensitive to apoptosis induced by caspase-8 over expression, suggesting that the mutation reduced caspase-8 activity. Caspase-8 mutations have also been identified in hepatocellular and gastric carcinomas with defective apoptosis activities observed in mutants [26, 27]. Five caspase-8 mutations were identified in invasive colorectal carcinomas that include three missense mutations, one frame-shift mutation, and one nonsense mutation [28]. 293T cells transfected with mutant caspase-8 expression vectors showed decreased apoptosis after DR5 overexpression. Collectively theses studies highlight that caspase-8 mutations are present in a variety of malignancies and these mutations inactivate the cysteine protease and lead to reduced spontaneous and receptor mediated-cell death.

Decreased caspase-8 expression and epige­netic silencing

The previously mentioned studies detected caspase-8 mutations in malignant cells yet these mutations were not associated with loss of caspase-8 expression. Dual observations of caspase-8 mutation and undetectable caspase-8 expression have been noted in HOC313 head and neck carcinoma cells [29]. Chemoresistance to the anti-cancer drug cisplatin was also observed in HOC313 cells. Loss of caspase-8 expression has been described in childhood neuroblastomas and medulloblastomas insensitive to TRAIL-induced cell death. Treatment with DNA methyltransferase inhibitor 5’Aza-deoxycytidine (5-Aza) increased caspase-8 mRNA and protein expression in both TRAIL-resistant neuroblastoma [30, 31] and medulloblastoma [32, 33] cancer cells, suggesting that epigenetic silencing was responsible for the downregulation of caspase-8. Increased caspase-8 expression was associated with enhanced TRAIL-mediated cell death. Further investigation of TRAIL-resistant neuroblastoma revealed that invasive neuroblastoma cells have increased TRAIL resistance and decreased caspase-8 mRNA and protein compared to non-invasive neuroblastoma cell lines [31]. Treatment of invasive neuroblastoma cells with DNA methyltransferase inhibitor Azacytidine, increased caspase-8 protein expression and increased cell death after co-treatment of Azacytidine and TRAIL. Silencing of caspase-8 expression by DNA methylation has also been noted in small cell lung carcinoma [34]. 5-Aza treatment also increased caspase-8 protein expression and improved TRAIL sensitivity.

DNA hypermethylation is not the only epigenetic mechanism found to be responsible for decreased caspase-8 expression. Histone hypoacetylation has also been found to result in caspase-8 downregulation. Medulloblastoma cell treatment with histone deacetylase (HDAC) inhibitors valproic acid (VA) and suberoylanilide hydroxamic acid (SAHA) also increased caspase-8 expression [35].

These reports underline caspase-8 epigenetic silencing by DNA methylation as a means for malignant cancer cells to decrease caspase-8 expression and avoid TRAIL-induced cell death. TRAIL resistance noted by epigenetic silencing of caspase-8, emphasizes the requirement of caspase-8 expression for complete TRAIL signaling. Modulation of caspase-8 has been studied to define treatments that increase caspase-8 expression and thus enhance TRAIL-mediated cell death.

Cytokine Interferon gamma (IFNγ) was previously shown to increase TRAIL sensitivity in a dose-dependent manner in Ewing sarcoma, neuroblastoma, and medulloblastoma cells [36]. Further examination revealed increased caspase-8 expression, but not effector caspase-3 expression, after treatment with IFNγ. Co-treatment with TRAIL and IFNγ resulted in markedly enhanced caspase-mediated cell death. IFNγ mediated caspase-upregulation was found to be Stat1 dependent [36]. IFNγ treatment did not change the methylation status of caspase-8 [36].

Decreased caspase-8 stability

Decreased caspase-8 stability and accele­rated degradation has been reported in TRAIL resistant DLD1 colon cancer cells [37]. Restoration of caspase-8 expression in resistant DLD1 cells resulted in increased TRAIL-induced apoptosis. Caspase-8-and caspase-10-associated RING proteins, CARP1 and CARP2 mRNA were upregulated in TRAIL-resistant colon cancer cells compared to TRAIL-sensitive parental cells. CARP1 and CARP2 aid in ubiquitin-mediated proteolysis of death effector domain containing caspases [38].

Proteasome inhibitor stabilization of caspase-8 remains controversial. Caspase-8 stabilization after proteasome inhibition has been noted in some cancer cells [39]. Conversely, caspase-8 expression was unchanged in ovarian carcinoma cells after treatment with the proteasome inhibitor MG132 [40]. These differences may be cell type dependent. Additionally, autophagic lysosomal caspase-8 degradation has also been described [41].

Caspase-8 ubiquitination

Several caspase-8 post-translational modifications have been identified including caspase-8 phosphorylation and ubiquitination. Caspase-8 phosphorylation has been noted on various residues (Thr263, Tyr380, Tyr397, Tyr645) [42–47]. Caspase-8 phosphorylation is reported to inhibit caspase-8 activity. Yet, caspase-8 phosphorylation status in TRAIL-resistant cancer cells has not been thoroughly explored. In 2009, Jin and colleagues revealed that TRAIL treatment induces caspase-8 ubiquitination in TRAIL-sensitive H460 lung cancer cells [48]. The E3 ligase CUL3 was shown to interact with caspase-8 and was associated with the DISC after TRAIL treatment. Knockdown of CUL3 decreased caspase-8 ubiquitination and activity and limited TRAIL-mediated apoptosis. TRAIL treatment caused both K48 and K63 polyubiquitination chains to be added to caspase-8 [48]. Additio­nally, Jin et al. reported that ubiquitin binding protein p62 promoted TRAIL-induced caspase-8 aggregation. siRNA knockdown of p62 diminished TRAIL-induced caspase-8 ubiquitination and activity. No caspase-8 ubiquitination and processing was observed in two TRAIL-resistant cell lines, HeLa and ADR-RES [48]. This study highlights post-translational ubiquitination of caspase-8 for complete TRAIL sensitivity.

A recent report by Bellail and colleagues examined ubiquitin enzymes A20 and CUL3 in TRAIL-sensitive and TRAIL-resistant glioblastoma cell lines. Unlike H460 lung cancer cells, TRAIL-sensitive glioblastoma cells had no detectable caspase-8 ubiquitination or CUL3 in the DISC after TRAIL treatment [49]. Little A20 expression was detected in TRAIL-sensitive glioblastoma cells. Introduction of A20 expression plasmids reversed TRAIL sensitivity. The A20 zinc finger domain, that confers E3 ligase capability, was found to be necessary for A20-mediated TRAIL resistance [49]. Further investigation found that A20 attaches K63 polyubiquitin chains to RIP1 and these polyubiquitin chains interact with caspase-8. An in vitro caspase-8 cleavage assay revealed that K63 polyubiquitin chains inhibit caspase-8 processing [49]. These stu­dies show how in two different malignant cell types, direct caspase-8 ubiquitination or association with a polyubi­quitinated protein can enhance or inhibit TRAIL-mediated cell death, respectively. In TRAIL-sensitive H460 lung cancer cells, caspase-8 is ubiquitinated and undergoes aggregation required for complete caspase-8 activation and activation of downstream caspase cascade (Fig. 2). In TRAIL-resistant glioblastomas, caspase-8 interacts with A20-induced K63 polyubiquitin chains attached to RIP1 that hinder caspase-8 activation and processing (Fig. 3).

 Caspase 8 regulation of TRAIL mediated cell death
Fig. 2. Schematic of TRAIL susceptibility after caspase-8 poly­ubiquitination. (Left; Example TRAIL-sensitive H460 cells) TRAIL ligation to a pro-apoptotic TRAIL receptor causes E3 Ligase CUL3 to polyubiquitinate caspase-8. Ubiquitinated caspase-8 can properly aggregate and complete caspase-8 and caspase-3 activation leads to cell death. (Right; Example TRAIL-resistant HeLa cells) Caspase-8 that is not ubiquitinated cannot be fully activated which leads to failure to activate caspase-3 and cause cell death
 Caspase 8 regulation of TRAIL mediated cell death
Fig. 3. Schematic of TRAIL resistance after caspase-8 association with polyubiquitinated RIP1. (Left; Example of TRAIL-sensitive glioblastoma cells LN71) TRAIL ligation causes activation of initiator caspase-8 and effector caspase-3, leading to cell death. (Right; Example of TRAIL-resistant glioblastoma cells LN443) The E3 ligase zinc finger domain of A20 polyubiquitinates RIP1. Caspase-8 interacts with polyubiquitinated RIP1. Polyubiquitinated RIP1 inhibits caspase-8 processing and subsequent signaling of apoptosis

Concluding remarks

TRAIL susceptibility in malignant cells is the foundation for various TRAIL-based therapies currently being explored for translational use. Yet, not all cancer cells are sensitive to TRAIL-induced cell death. It is not hard to imagine that cancer cells have acquired mechanism(s) that escape TRAIL immunosurveillance and inhibit cell death. Abnormalities in expression and activation status of the upstream executioner caspase-8 are detailed in this review. Restoration of caspase-8 expression or activity sensitizes various TRAIL-resistant cancer cells. Future studies focusing on modulation of caspase-8 expression and upregulation will further contribute to the scientific knowledge of molecular determinants that confer TRAIL resistance and will likely aid in the efficacy of TRAIL-based therapies.

REFERENCES

1. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3: 673–82.
2. Pitti RM, Marsters SA, Ruppert S, et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996; 271: 12687–90.
3. Pan G, Ni J, Wei YF, et al. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 1997; 277: 815–8.
4. Wu GS, Burns TF, McDonald ER 3rd, et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 1997; 17: 141–3.
5. MacFarlane M, Ahmad M, Srinivasula SM, et al. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J Biol Chem 1997; 272: 25417–20.
6. Sheridan JP, Marsters SA, Pitti RM, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997; 277: 818–21.
7. Marsters SA, Sheridan JP, Pitti RM, et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol 1997; 7: 1003–6.
8. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273: 14363–7.
9. Falschlehner C, Schaefer U, Walczak H. Following TRAIL’s path in the immune system. Immunology 2009; 127: 145–54.
10. Jin Z, McDonald ER 3rd, Dicker DT, El-Deiry WS. Deficient tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor transport to the cell surface in human colon cancer cells selected for resistance to TRAIL-induced apoptosis. J Biol Chem 2004; 279: 35829–39.
11. Wagner KW, Punnoose EA, Januario T, et al. Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL. Nat Med 2007; 13: 1070–7.
12. Krueger A, Baumann S, Krammer PH, Kirchhoff S. FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol 2001; 21: 8247–54.
13. Safa AR. c-FLIP: A master anti-apoptotic regulator. Exp Oncol 2012; 34: 176–184.
14. Ricci MS, Jin Z, Dews M, et al. Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity. Mol Cell Biol 2004; 24: 8541–55.
15. Ricci MS, Kim SH, Ogi K, et al. Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. Cancer Cell 2007; 12: 66–80.
16. Kischkel FC, Lawrence DA, Tinel A, et al. Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. J Biol Chem 2001; 276: 46639–46.
17. Sprick MR, Rieser E, Stahl H, et al. Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8. EMBO J 2002; 21: 4520–30.
18. Fulda S. Caspase-8 in cancer biology and therapy. Cancer Lett 2009; 281: 128–33.
19. Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene 2003; 22: 8543–67.
20. Scaffidi C, Medema JP, Krammer PH, Peter ME. FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b. J Biol Chem 1997; 272: 26953–8.
21. Horiuchi T, Himeji D, Tsukamoto H, et al. Dominant expression of a novel splice variant of caspase-8 in human peripheral blood lymphocytes. Biochem Biophys Res Commun 2000; 272: 877–81.
22. Himeji D, Horiuchi T, Tsukamoto H, et al. Characteri­zation of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood 2002; 99: 4070–8.
23. Piras V, Hayashi K, Tomita M, Selvarajoo K. Enhancing apoptosis in TRAIL-resistant cancer cells using fundamental response rules. Sci Rep 2011; 1: 144.
24. Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther 2005; 4: 139–63.
25. Mandruzzato S, Brasseur F, Andry G, et al. A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma. J Exp Med 1997; 186: 785–93.
26. Soung YH, Lee JW, Kim SY, et al. CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas. Cancer Res 2005; 65: 815–21.
27. Soung YH, Lee JW, Kim SY, et al. Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas. Oncogene 2005; 24: 141–7.
28. Kim HS, Lee JW, Soung YH, et al. Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology 2003; 125: 708–15.
29. Liu J, Uematsu H, Tsuchida N, Ikeda MA. Association of caspase-8 mutation with chemoresistance to cisplatin in HOC313 head and neck squamous cell carcinoma cells. Biochem Biophys Res Commun 2009; 390: 989–94.
30. Eggert A, Grotzer MA, Zuzak TJ, et al. Resistance to TRAIL-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Med Pediatr Oncol 2000; 35: 603–7.
31. Hopkins-Donaldson S, Bodmer JL, Bourloud KB, et al. Loss of caspase-8 expression in highly malignant human neuroblastoma cells correlates with resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 2000; 60: 4315–9.
32. Grotzer MA, Eggert A, Zuzak TJ, et al. Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. Oncogene 2000; 19: 4604–10.
33. Zuzak TJ, Steinhoff DF, Sutton LN, et al. Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumour/medulloblastoma. Eur J Cancer 2002; 38: 83–91.
34. Hopkins-Donaldson S, Ziegler A, Kurtz S, et al. Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation. Cell Death Differ 2003; 10: 356–64.
35. Hacker S, Dittrich A, Mohr A, et al. Histone deacetylase inhibitors cooperate with IFN-gamma to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8. Oncogene 2009; 28: 3097–110.
36. Fulda S, Debatin KM. IFN gamma sensitizes for apoptosis by upregulating caspase-8 expression through the Stat1 pathway. Oncogene 2002; 21: 2295–308.
37. Zhang L, Zhu H, Teraishi F, et al. Accelerated degradation of caspase-8 protein correlates with TRAIL resistance in a DLD1 human colon cancer cell line. Neoplasia 2005; 7: 594–602.
38. McDonald ER 3rd, El-Deiry WS. Suppression of caspase-8- and -10-associated RING proteins results in sensitization to death ligands and inhibition of tumor cell growth. Proc Natl Acad Sci USA 2004; 101: 6170–5.
39. van Geelen CM, Pennarun B, Ek WB, et al. Downregulation of active caspase-8 as a mechanism of acquired TRAIL resistance in mismatch repair-proficient colon carcinoma cell lines. Int J Oncol 2010; 37: 1031–41.
40. Duiker EW, Meijer A, van der Bilt AR, et al. Drug-induced caspase-8 upregulation sensitises cisplatin-resistant ovarian carcinoma cells to rhTRAIL-induced apoptosis. Br J Cancer 2011; 104: 1278–87.
41. Hou W, Han J, Lu C, et al. Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. Autophagy 2010; 6: 891–900.
42. Peng C, Cho YY, Zhu F, et al. Phosphorylation of caspase-8 (Thr-263) by ribosomal S6 kinase 2 (RSK2) mediates caspase-8 ubiquitination and stability. J Biol Chem 2011; 286: 6946–54.
43. Kurokawa M, Kornbluth S. Caspases and kinases in a death grip. Cell 2009; 138: 838–54.
44. Cursi S, Rufini A, Stagni V, et al. Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression. EMBO J 2006; 25: 1895–905.
45. Senft J, Helfer B, Frisch SM. Caspase-8 interacts with the p85 subunit of phosphatidylinositol 3-kinase to regulate cell adhesion and motility. Cancer Res 2007; 67: 11505–9.
46. Barbero S, Barila D, Mielgo A, et al. Identification of a critical tyrosine residue in caspase-8 that promotes cell migration. J Biol Chem 2008; 283: 13031–4.
47. Jia SH, Parodo J, Kapus A, et al. Dynamic regulation of neutrophil survival through tyrosine phosphorylation or dephosphorylation of caspase-8. J Biol Chem 2008; 283: 5402–13.
48. Jin Z, Li Y, Pitti R, et al. Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 2009; 137: 721–35.
49. Bellail AC, Olson JJ, Yang X, et al. A20 Ubiquitin ligase-mediated polyubiquitination of RIP1 inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma. Cancer Discov 2012; 2: 140–55.

No Comments » Add comments
Leave a comment

ERROR: si-captcha.php plugin says GD image support not detected in PHP!

Contact your web host and ask them why GD image support is not enabled for PHP.

ERROR: si-captcha.php plugin says imagepng function not detected in PHP!

Contact your web host and ask them why imagepng function is not enabled for PHP.