Abstract
Death receptor-induced apoptosis is triggered by the activation of caspase-8 and caspase-10. Caspase cleavage in the DISC is regulated by c-FLIP proteins, which exist in long (c-FLIPL) or truncated short isoforms (c-FLIPS/R). The latter inhibit the activation of caspase-8, whereas c-FLIPL can heterodimerize to partially process the caspase, which then induces non-apoptotic signaling pathways. Evidently, the expression levels of different c-FLIP isoforms are crucial for the cell’s decision to die or survive and various post-translational modifications are employed to accommodate the balance. We demonstrated that c-FLIP phosphorylation by PKC on serine 193 can inhibit the protein from being ubiquitylated. This protects c-FLIPS/R from proteasomal degradation, whereas the detailed role of the S193 phosphorylation of c-FLIPL is yet to be determined.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Boatright KM, Salvesen GS (2003) Mechanisms of caspase activation. Curr Opin Cell Biol 15(6):725–731
Chang L, Kamata H, Solinas G, Luo JL, Maeda S, Venuprasad K, Liu YC, Karin M (2006) The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 124(3):601–613
Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM (1995) FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81(4):505–512
Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116(2):205–219
Djerbi M, Darreh-Shori T, Zhivotovsky B, Grandien A (2001) Characterization of the human FLICE-inhibitory protein locus and comparison of the anti-apoptotic activity of four different flip isoforms. Scand J Immunol 54(1–2):180–189
Fukazawa T, Fujiwara T, Uno F, Teraishi F, Kadowaki Y, Itoshima T, Takata Y, Kagawa S, Roth JA, Tschopp J, Tanaka N (2001) Accelerated degradation of cellular FLIP protein through the ubiquitin–proteasome pathway in p53-mediated apoptosis of human cancer cells. Oncogene 20(37):5225–5231
Golks A, Brenner D, Fritsch C, Krammer PH, Lavrik IN (2005) c-FLIPR, a new regulator of death receptor-induced apoptosis. J Biol Chem 280(15):14507–14513
Gutcher I, Webb PR, Anderson NG (2003) The isoform-specific regulation of apoptosis by protein kinase C. Cell Mol Life Sci 60(6):1061–1070
Higuchi H, Yoon JH, Grambihler A, Werneburg N, Bronk SF, Gores GJ (2003) Bile acids stimulate cFLIP phosphorylation enhancing TRAIL-mediated apoptosis. J Biol Chem 278(1):454–461
Ikeda F, Dikic I (2008) Atypical ubiquitin chains: new molecular signals. ‘protein modifications: Beyond the usual suspects’ review series. EMBO Rep 9(6):536–542
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schröter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388(6638):190–195
Kaunisto A, Kochin V, Asaoka T, Mikhailov A, Poukkula M, Meinander A, Eriksson JE (2009) PKC-mediated phosphorylation regulates c-FLIP ubiquitylation and stability. Cell Death Differ 16(9):1215–1226
Kundu M, Pathak SK, Kumawat K, Basu S, Chatterjee G, Pathak S, Noguchi T, Takeda K, Ichijo H, Thien CB, Langdon WY, Basu J (2009) A TNF- and c-cbl-dependent FLIP(S)-degradation pathway and its function in mycobacterium tuberculosis-induced macrophage apoptosis. Nat Immunol 10(8):918–926
Meinander A, Söderström TS, Kaunisto A, Poukkula M, Sistonen L, Eriksson JE (2007) Fever-like hyperthermia controls T lymphocyte persistence by inducing degradation of cellular FLIPshort. J Immunol 178(6):3944–3953
Perez D, White E (2003) E1A sensitizes cells to tumor necrosis factor alpha by downregulating c-FLIP S. J Virol 77(4):2651–2662
Poukkula M, Kaunisto A, Hietakangas V, Denessiouk K, Katajamäki T, Johnson MS, Sistonen L, Eriksson JE (2005) Rapid turnover of c-FLIPshort is determined by its unique C-terminal tail. J Biol Chem 280(29):27345–27355
Scaffidi C, Schmitz I, Krammer PH, Peter ME (1999) The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 274(3):1541–1548
Shi B, Tran T, Sobkoviak R, Pope RM (2009) Activation-induced degradation of FLIPL is mediated via the phosphatidylinositol 3-Kinase/Akt signaling pathway in macrophages. J Biol Chem 284(21):14513–14523
Shu HB, Halpin DR, Goeddel DV (1997) Casper is a FADD- and caspase-related inducer of apoptosis. Immunity 6(6):751–763
Ueffing N, Keil E, Freund C, Kühne R, Schulze-Osthoff K, Schmitz I (2008) Mutational analyses of c-FLIPR, the only murine short FLIP isoform, reveal requirements for DISC recruitment. Cell Death Differ 15(4):773–782
Xiao C, Yang BF, Song JH, Schulman H, Li L, Hao C (2005) Inhibition of CaMKII-mediated c-FLIP expression sensitizes malignant melanoma cells to TRAIL-induced apoptosis. Exp Cell Res 304(1):244–255
Yang BF, Xiao C, Roa WH, Krammer PH, Hao C (2003) Calcium/calmodulin-dependent protein kinase II regulation of c-FLIP expression and phosphorylation in modulation of fas-mediated signaling in malignant glioma cells. J Biol Chem 278(9):7043–7050
Yu JW, Jeffrey PD, Shi Y (2009) Mechanism of procaspase-8 activation by c-FLIPL. Proc Natl Acad Sci USA 106(20):8169–8167
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this paper
Cite this paper
Asaoka, T., Kaunisto, A., Eriksson, J.E. (2011). Regulation of Cell Death by c-FLIP Phosphorylation. In: Wallach, D., Kovalenko, A., Feldmann, M. (eds) Advances in TNF Family Research. Advances in Experimental Medicine and Biology, vol 691. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6612-4_66
Download citation
DOI: https://doi.org/10.1007/978-1-4419-6612-4_66
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-6611-7
Online ISBN: 978-1-4419-6612-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)