Cytokine–Cytokine Cross Talk and Cell-Death Decisions

  • Christopher D. Deppmann
  • Kevin A. Janes


Cells often face life or death decisions in response to conflicting extracellular cytokine cues. A full understanding of how this information is encoded has implications for normal development and function of organ systems and also for pathologies where cues are not processed properly. In this chapter, we discuss how life–death decisions are influenced by signaling from pro-survival receptor tyrosine kinases (RTKs) and pro-death tumor necrosis factor (TNF)-family receptors. Intracellular cross talk between these antagonistic receptors is incredibly complex, and our understanding could be improved by systems biology thinking and approaches. We describe key systems-level features of RTK and TNF-family receptor signaling and how points of cross talk may mediate the decision to live or die.


Cross Talk Boolean Network Fuzzy Logic Model Tumor Necrosis Factor Family Cytokine Combination 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Akca H, Akan SY, Yanikoglu A, Ozes ON (2003) Suppression of TNF-α mediated apoptosis by EGF in TNF-α sensitive human cervical carcinoma cell line. Growth Factors 21:31–39PubMedGoogle Scholar
  2. Albeck JG, MacBeath G, White FM, Sorger PK, Lauffenburger DA, Gaudet S (2006) Collecting and organizing systematic sets of protein data. Nat Rev Mol Cell Biol 7:803–812PubMedGoogle Scholar
  3. Aldridge BB, Burke JM, Lauffenburger DA, Sorger PK (2006) Physicochemical modelling of cell signalling pathways. Nat Cell Biol 8:1195–1203PubMedGoogle Scholar
  4. Aldridge BB, Saez-Rodriguez J, Muhlich JL, Sorger PK, Lauffenburger DA (2009) Fuzzy logic analysis of kinase pathway crosstalk in TNF/EGF/insulin-induced signaling. PLoS Comput Biol 5:e1000340PubMedGoogle Scholar
  5. Alexopoulou L, Kranidioti K, Xanthoulea S, Denis M, Kotanidou A, Douni E, Blackshear PJ, Kontoyiannis DL, Kollias G (2006) Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity. Eur J Immunol 36:2768–2780PubMedGoogle Scholar
  6. Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR (2003) Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol 5:647–654PubMedGoogle Scholar
  7. Altieri DC (2003) Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3:46–54PubMedGoogle Scholar
  8. Amit I, Citri A, Shay T, Lu Y, Katz M, Zhang F, Tarcic G, Siwak D, Lahad J, Jacob-Hirsch J et al (2007) A module of negative feedback regulators defines growth factor signaling. Nat Genet 39:503–512PubMedGoogle Scholar
  9. Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308PubMedGoogle Scholar
  10. Avraham R, Yarden Y (2011) Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat Rev Mol Cell Biol 12:104–117PubMedGoogle Scholar
  11. Bamji SX, Majdan M, Pozniak CD, Belliveau D, Aloyz R, Kohn J, Causing CG, Miller FD (1998) The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. J Cell Biol 140:911–923PubMedGoogle Scholar
  12. Bange J, Zwick E, Ullrich A (2001) Molecular targets for breast cancer therapy and prevention. Nat Med 7:548–552PubMedGoogle Scholar
  13. Beattie MS, Harrington AW, Lee R, Kim JY, Boyce SL, Longo FM, Bresnahan JC, Hempstead BL, Yoon SO (2002) ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36:375–386PubMedGoogle Scholar
  14. Bedard S, Marcotte B, Marette A (1998) Insulin inhibits inducible nitric oxide synthase in skeletal muscle cells. Diabetologia 41:1523–1527PubMedGoogle Scholar
  15. Bhalla US, Iyengar R (1999) Emergent properties of networks of biological signaling pathways. Science 283:381–387PubMedGoogle Scholar
  16. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365PubMedGoogle Scholar
  17. Borisov N, Aksamitiene E, Kiyatkin A, Legewie S, Berkhout J, Maiwald T, Kaimachnikov NP, Timmer J, Hoek JB, Kholodenko BN (2009) Systems-level interactions between insulin-EGF networks amplify mitogenic signaling. Mol Syst Biol 5:256PubMedGoogle Scholar
  18. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868PubMedGoogle Scholar
  19. Canault M, Peiretti F, Mueller C, Kopp F, Morange P, Rihs S, Portugal H, Juhan-Vague I, Nalbone G (2004) Exclusive expression of transmembrane TNF-α in mice reduces the inflammatory response in early lipid lesions of aortic sinus. Atherosclerosis 172:211–218PubMedGoogle Scholar
  20. Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240–4245PubMedGoogle Scholar
  21. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321PubMedGoogle Scholar
  22. Chailler P, Menard D (1999) Ontogeny of EGF receptors in the human gut. Front Biosci 4:D87–101PubMedGoogle Scholar
  23. Chatterjee MS, Purvis JE, Brass LF, Diamond SL (2010) Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli. Nat Biotechnol 28:727–732PubMedGoogle Scholar
  24. Chen WN, Woodbury RL, Kathmann LE, Opresko LK, Zangar RC, Wiley HS, Thrall BD (2004) Induced autocrine signaling through the epidermal growth factor receptor contributes to the response of mammary epithelial cells to tumor necrosis factor alpha. J Biol Chem 279:18488–18496PubMedGoogle Scholar
  25. Cheng CS, Feldman KE, Lee J, Verma S, Huang DB, Huynh K, Chang M, Ponomarenko JV, Sun SC, Benedict CA et al (2011) The specificity of innate immune responses is enforced by repression of interferon response elements by NF-κB p50. Sci Signal 4:ra11PubMedGoogle Scholar
  26. Cohen-Saidon C, Cohen AA, Sigal A, Liron Y, Alon U (2009) Dynamics and variability of ERK2 response to EGF in individual living cells. Mol Cell 36:885–893PubMedGoogle Scholar
  27. Cosgrove BD, Cheng C, Pritchard JR, Stolz DB, Lauffenburger DA, Griffith LG (2008) An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha. Hepatology 48:276–288PubMedGoogle Scholar
  28. Covert MW, Leung TH, Gaston JE, Baltimore D (2005) Achieving stability of lipopolysaccharide-induced NF-κB activation. Science 309:1854–1857PubMedGoogle Scholar
  29. Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM, Datta SR, Greenberg ME, Licklider LJ, Lowell BB et al (2003) BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424:952–956PubMedGoogle Scholar
  30. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241PubMedGoogle Scholar
  31. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927PubMedGoogle Scholar
  32. Datta SR, Ranger AM, Lin MZ, Sturgill JF, Ma YC, Cowan CW, Dikkes P, Korsmeyer SJ, Greenberg ME (2002) Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev Cell 3:631–643PubMedGoogle Scholar
  33. Delhase M, Li N, Karin M (2000) Kinase regulation in inflammatory response. Nature 406:367–368PubMedGoogle Scholar
  34. Deng J, Miller SA, Wang HY, Xia W, Wen Y, Zhou BP, Li Y, Lin SY, Hung MC (2002) β-Catenin interacts with and inhibits NF-κ B in human colon and breast cancer. Cancer Cell 2:323–334PubMedGoogle Scholar
  35. Deppmann CD, Mihalas S, Sharma N, Lonze BE, Niebur E, Ginty DD (2008) A model for neuronal competition during development. Science 320:369–373PubMedGoogle Scholar
  36. DeWitt AE, Dong JY, Wiley HS, Lauffenburger DA (2001) Quantitative analysis of the EGF receptor autocrine system reveals cryptic regulation of cell response by ligand capture. J Cell Sci 114:2301–2313PubMedGoogle Scholar
  37. Downward J (2001) The ins and outs of signalling. Nature 411:759–762PubMedGoogle Scholar
  38. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043PubMedGoogle Scholar
  39. Fan H, Derynck R (1999) Ectodomain shedding of TGF-α and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades. EMBO J 18:6962–6972PubMedGoogle Scholar
  40. Fernandez-Marcos PJ, Abu-Baker S, Joshi J, Galvez A, Castilla EA, Canamero M, Collado M, Saez C, Moreno-Bueno G, Palacios J et al (2009) Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-κB activation and invasive prostate carcinoma. Proc Natl Acad Sci USA 106:12962–12967PubMedGoogle Scholar
  41. Franke TF, Kaplan DR, Cantley LC (1997) PI3K: downstream AKTion blocks apoptosis. Cell 88:435–437PubMedGoogle Scholar
  42. Garcia-Lloret MI, Yui J, Winkler-Lowen B, Guilbert LJ (1996) Epidermal growth factor inhibits cytokine-induced apoptosis of primary human trophoblasts. J Cell Physiol 167:324–332PubMedGoogle Scholar
  43. Garmaroudi FS, Marchant D, Si X, Khalili A, Bashashati A, Wong BW, Tabet A, Ng RT, Murphy K, Luo H et al (2010) Pairwise network mechanisms in the host signaling response to coxsackie virus B3 infection. Proc Natl Acad Sci USA 107:17053–17058PubMedGoogle Scholar
  44. Gaudet S, Janes KA, Albeck JG, Pace EA, Lauffenburger DA, Sorger PK (2005) A compendium of signals and responses triggered by prodeath and prosurvival cytokines. Mol Cell Proteomics 4:1569–1590PubMedGoogle Scholar
  45. Gibson S, Tu S, Oyer R, Anderson SM, Johnson GL (1999) Epidermal growth factor protects epithelial cells against Fas-induced apoptosis requirement for Akt activation. J Biol Chem 274:17612–17618PubMedGoogle Scholar
  46. Goetze S, Blaschke F, Stawowy P, Bruemmer D, Spencer C, Graf K, Grafe M, Law RE, Fleck E (2001) TNFalpha inhibits insulin’s antiapoptotic signaling in vascular smooth muscle cells. Biochem Biophys Res Commun 287:662–670PubMedGoogle Scholar
  47. Gordus A, Krall JA, Beyer EM, Kaushansky A, Wolf-Yadlin A, Sevecka M, Chang BH, Rush J, MacBeath G (2009) Linear combinations of docking affinities explain quantitative differences in RTK signaling. Mol Syst Biol 5:235PubMedGoogle Scholar
  48. Graham NA, Asthagiri AR (2004) Epidermal growth factor-mediated T-cell factor/lymphoid enhancer factor transcriptional activity is essential but not sufficient for cell cycle progression in nontransformed mammary epithelial cells. J Biol Chem 279:23517–23524PubMedGoogle Scholar
  49. Gustin JA, Ozes ON, Akca H, Pincheira R, Mayo LD, Li Q, Guzman JR, Korgaonkar CK, Donner DB (2004) Cell type-specific expression of the IkappaB kinases determines the significance of phosphatidylinositol 3-kinase/Akt signaling to NF-κ B activation. J Biol Chem 279:1615–1620PubMedGoogle Scholar
  50. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedGoogle Scholar
  51. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedGoogle Scholar
  52. Holtmann MH, Neurath MF (2004) Differential TNF-signaling in chronic inflammatory disorders. Curr Mol Med 4:439–444PubMedGoogle Scholar
  53. Howard PL, Chia MC, Del Rizzo S, Liu FF, Pawson T (2003) Redirecting tyrosine kinase signaling to an apoptotic caspase pathway through chimeric adaptor proteins. Proc Natl Acad Sci USA 100:11267–11272PubMedGoogle Scholar
  54. Hsueh RC, Natarajan M, Fraser I, Pond B, Liu J, Mumby S, Han H, Jiang LI, Simon MI, Taussig R et al (2009) Deciphering signaling outcomes from a system of complex networks. Sci Signal 2:ra22PubMedGoogle Scholar
  55. Huse M, Kuriyan J (2002) The conformational plasticity of protein kinases. Cell 109:275–282PubMedGoogle Scholar
  56. Idriss HT, Naismith JH (2000) TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 50:184–195PubMedGoogle Scholar
  57. Janes KA (2010) Paring down signaling complexity. Nat Biotechnol 28:681–682PubMedGoogle Scholar
  58. Janes KA, Lauffenburger DA (2006) A biological approach to computational models of proteomic networks. Curr Opin Chem Biol 10:73–80PubMedGoogle Scholar
  59. Janes KA, Yaffe MB (2006) Data-driven modelling of signal-transduction networks. Nat Rev Mol Cell Biol 7:820–828PubMedGoogle Scholar
  60. Janes KA, Albeck JG, Gaudet S, Sorger PK, Lauffenburger DA, Yaffe MB (2005) A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis. Science 310:1646–1653PubMedGoogle Scholar
  61. Janes KA, Gaudet S, Albeck JG, Nielsen UB, Lauffenburger DA, Sorger PK (2006) The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell 124:1225–1239PubMedGoogle Scholar
  62. Janes KA, Reinhardt HC, Yaffe MB (2008) Cytokine-induced signaling networks prioritize dynamic range over signal strength. Cell 135:343–354PubMedGoogle Scholar
  63. Janeway CA, Travers P, Walport M, Shlomchik MJ (2001) Immunobiology, 5th edn. Garland, New YorkGoogle Scholar
  64. Jay SM, Kurtagic E, Alvarez LM, de Picciotto S, Sanchez E, Hawkins JF, Prince RN, Guerrero Y, Treasure CL, Lee RT et al (2011) Engineered bivalent ligands to bias ErbB receptor-mediated signaling and phenotypes. J Biol Chem 286:27729–40PubMedGoogle Scholar
  65. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J et al (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968–972PubMedGoogle Scholar
  66. Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[κ]B activity. Annu Rev Immunol 18:621–663PubMedGoogle Scholar
  67. Kasibhatla S, Brunner T, Genestier L, Echeverri F, Mahboubi A, Green DR (1998) DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-κ B and AP-1. Mol Cell 1:543–551PubMedGoogle Scholar
  68. Kenchappa RS, Tep C, Korade Z, Urra S, Bronfman FC, Yoon SO, Carter BD (2010) p75 Neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-alpha-converting enzyme/ADAM17. J Biol Chem 285:20358–20368PubMedGoogle Scholar
  69. Kim S, Domon-Dell C, Kang J, Chung DH, Freund JN, Evers BM (2004) Down-regulation of the tumor suppressor PTEN by the tumor necrosis factor-alpha/nuclear factor-κB (NF-κB)-inducing kinase/NF-κB pathway is linked to a default IκB-α autoregulatory loop. J Biol Chem 279:4285–4291PubMedGoogle Scholar
  70. Kim T, Yoon J, Cho H, Lee WB, Kim J, Song YH, Kim SN, Yoon JH, Kim-Ha J, Kim YJ (2005) Downregulation of lipopolysaccharide response in Drosophila by negative crosstalk between the AP1 and NF-κB signaling modules. Nat Immunol 6:211–218PubMedGoogle Scholar
  71. Kohn J, Aloyz RS, Toma JG, Haak-Frendscho M, Miller FD (1999) Functionally antagonistic interactions between the TrkA and p75 neurotrophin receptors regulate sympathetic neuron growth and target innervation. J Neurosci 19:5393–5408PubMedGoogle Scholar
  72. Kumar D, Srikanth R, Ahlfors H, Lahesmaa R, Rao KV (2007) Capturing cell-fate decisions from the molecular signatures of a receptor-dependent signaling response. Mol Syst Biol 3:150PubMedGoogle Scholar
  73. LaCasse EC, Baird S, Korneluk RG, MacKenzie AE (1998) The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 17:3247–3259PubMedGoogle Scholar
  74. Lauffenburger DA, Forsten KE, Will B, Wiley HS (1995) Molecular/cell engineering approach to autocrine ligand control of cell function. Ann Biomed Eng 23:208–215PubMedGoogle Scholar
  75. Lavrik I, Golks A, Krammer PH (2005) Death receptor signaling. J Cell Sci 118:265–267PubMedGoogle Scholar
  76. Lebrun-Julien F, Bertrand MJ, De Backer O, Stellwagen D, Morales CR, Di Polo A, Barker PA (2010) ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway. Proc Natl Acad Sci USA 107:3817–3822PubMedGoogle Scholar
  77. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141:1117–1134PubMedGoogle Scholar
  78. Li ZW, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M, Johnson R, Karin M (1999) The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 189:1839–1845PubMedGoogle Scholar
  79. Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487–501PubMedGoogle Scholar
  80. Majdan M, Walsh GS, Aloyz R, Miller FD (2001) TrkA mediates developmental sympathetic neuron survival in vivo by silencing an ongoing p75NTR-mediated death signal. J Cell Biol 155:1275–1285PubMedGoogle Scholar
  81. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934PubMedGoogle Scholar
  82. McKay MM, Morrison DK (2007) Integrating signals from RTKs to ERK/MAPK. Oncogene 26:3113–3121PubMedGoogle Scholar
  83. Miller-Jensen K, Janes KA, Brugge JS, Lauffenburger DA (2007) Common effector processing mediates cell-specific responses to stimuli. Nature 448:604–608PubMedGoogle Scholar
  84. Modur V, Nagarajan R, Evers BM, Milbrandt J (2002) FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression Implications for PTEN mutation in prostate cancer. J Biol Chem 277:47928–47937PubMedGoogle Scholar
  85. Monine MI, Berezhkovskii AM, Joslin EJ, Wiley HS, Lauffenburger DA, Shvartsman SY (2005) Ligand accumulation in autocrine cell cultures. Biophys J 88:2384–2390PubMedGoogle Scholar
  86. Mueller C, Corazza N, Trachsel-Loseth S, Eugster HP, Buhler-Jungo M, Brunner T, Imboden MA (1999) Noncleavable transmembrane mouse tumor necrosis factor-alpha (TNFalpha) mediates effects distinct from those of wild-type TNFalpha in vitro and in vivo. J Biol Chem 274:38112–38118PubMedGoogle Scholar
  87. Natarajan M, Lin KM, Hsueh RC, Sternweis PC, Ranganathan R (2006) A global analysis of cross-talk in a mammalian cellular signalling network. Nat Cell Biol 8:571–580PubMedGoogle Scholar
  88. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H et al (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977PubMedGoogle Scholar
  89. Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981–989PubMedGoogle Scholar
  90. Obata T, Yaffe MB, Leparc GG, Piro ET, Maegawa H, Kashiwagi A, Kikkawa R, Cantley LC (2000) Peptide and protein library screening defines optimal substrate motifs for AKT/PKB. J Biol Chem 275:36108–36115PubMedGoogle Scholar
  91. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-κB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85PubMedGoogle Scholar
  92. Ozoren N, El-Deiry WS (2003) Cell surface death receptor signaling in normal and cancer cells. Semin Cancer Biol 13:135–147PubMedGoogle Scholar
  93. Pawson T, Scott JD (1997) Signaling through scaffold, anchoring, and adaptor proteins. Science 278:2075–2080PubMedGoogle Scholar
  94. Perkins ND (2004) NF-κB: tumor promoter or suppressor? Trends Cell Biol 14:64–69PubMedGoogle Scholar
  95. Perry RT, Collins JS, Wiener H, Acton R, Go RC (2001) The role of TNF and its receptors in Alzheimer’s disease. Neurobiol Aging 22:873–883PubMedGoogle Scholar
  96. Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, Huang A, Donahue CJ, Sherwood SW, Baldwin DT et al (1998) Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396:699–703PubMedGoogle Scholar
  97. Qian H, Hausman DB, Compton MM, Martin RJ, Della-Fera MA, Hartzell DL, Baile CA (2001) TNFalpha induces and insulin inhibits caspase 3-dependent adipocyte apoptosis. Biochem Biophys Res Commun 284:1176–1183PubMedGoogle Scholar
  98. Rodriguez J, Chen HH, Lin SC, Lazebnik Y (2000) Caspase phosphorylation, cell death, and species variability. Science 287:1363Google Scholar
  99. Rutgeerts P, Van Assche G, Vermeire S (2004) Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology 126:1593–1610PubMedGoogle Scholar
  100. Ruuls SR, Hoek RM, Ngo VN, McNeil T, Lucian LA, Janatpour MJ, Korner H, Scheerens H, Hessel EM, Cyster JG et al (2001) Membrane-bound TNF supports secondary lymphoid organ structure but is subservient to secreted TNF in driving autoimmune inflammation. Immunity 15:533–543PubMedGoogle Scholar
  101. Saez-Rodriguez J, Alexopoulos LG, Epperlein J, Samaga R, Lauffenburger DA, Klamt S, Sorger PK (2009) Discrete logic modelling as a means to link protein signalling networks with functional analysis of mammalian signal transduction. Mol Syst Biol 5:331PubMedGoogle Scholar
  102. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687PubMedGoogle Scholar
  103. Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225PubMedGoogle Scholar
  104. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM (2007) Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445:437–441PubMedGoogle Scholar
  105. Shao Z, Browning JL, Lee X, Scott ML, Shulga-Morskaya S, Allaire N, Thill G, Levesque M, Sah D, McCoy JM et al (2005) TAJ/TROY, an orphan TNF receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration. Neuron 45:353–359PubMedGoogle Scholar
  106. Sheikh MS, Huang Y, Fernandez-Salas EA, El-Deiry WS, Friess H, Amundson S, Yin J, Meltzer SJ, Holbrook NJ, Fornace AJ Jr (1999) The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene 18:4153–4159PubMedGoogle Scholar
  107. Sheng M, Greenberg ME (1990) The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 4:477–485PubMedGoogle Scholar
  108. Shvartsman SY, Hagan MP, Yacoub A, Dent P, Wiley HS, Lauffenburger DA (2002a) Autocrine loops with positive feedback enable context-dependent cell signaling. Am J Physiol Cell Physiol 282:C545–559PubMedGoogle Scholar
  109. Shvartsman SY, Muratov CB, Lauffenburger DA (2002b) Modeling and computational analysis of EGF receptor-mediated cell communication in Drosophila oogenesis. Development 129:2577–2589PubMedGoogle Scholar
  110. Singh P, Rubin N (1993) Insulin-like growth factors and binding proteins in colon cancer. Gastroenterology 105:1218–1237PubMedGoogle Scholar
  111. Song W, Volosin M, Cragnolini AB, Hempstead BL, Friedman WJ (2010) ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons. J Neurosci 30:15608–15615PubMedGoogle Scholar
  112. Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61:203–212PubMedGoogle Scholar
  113. Vilar M, Charalampopoulos I, Kenchappa RS, Simi A, Karaca E, Reversi A, Choi S, Bothwell M, Mingarro I, Friedman WJ et al (2009) Activation of the p75 neurotrophin receptor through conformational rearrangement of disulphide-linked receptor dimers. Neuron 62:72–83PubMedGoogle Scholar
  114. Wang Z, Cao N, Nantajit D, Fan M, Liu Y, Li JJ (2008) Mitogen-activated protein kinase phosphatase-1 represses c-Jun NH2-terminal kinase-mediated apoptosis via NF-κB regulation. J Biol Chem 283:21011–21023PubMedGoogle Scholar
  115. Ware CF (2005) Network communications: lymphotoxins, LIGHT, and TNF. Annu Rev Immunol 23:787–819PubMedGoogle Scholar
  116. Wehrman T, He X, Raab B, Dukipatti A, Blau H, Garcia KC (2007) Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors. Neuron 53:25–38PubMedGoogle Scholar
  117. Weiner FR, Smith PJ, Wertheimer S, Rubin CS (1991) Regulation of gene expression by insulin and tumor necrosis factor alpha in 3T3-L1 cells. Modulation of the transcription of genes encoding acyl-CoA synthetase and stearoyl-CoA desaturase-1. J Biol Chem 266:23525–23528PubMedGoogle Scholar
  118. Werner SL, Barken D, Hoffmann A (2005) Stimulus specificity of gene expression programs determined by temporal control of IKK activity. Science 309:1857–1861PubMedGoogle Scholar
  119. Wu Y, Tewari M, Cui S, Rubin R (1996) Activation of the insulin-like growth factor-I receptor inhibits tumor necrosis factor-induced cell death. J Cell Physiol 168:499–509PubMedGoogle Scholar
  120. Wu JJ, Roth RJ, Anderson EJ, Hong EG, Lee MK, Choi CS, Neufer PD, Shulman GI, Kim JK, Bennett AM (2006) Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. Cell Metab 4:61–73PubMedGoogle Scholar
  121. Yeh BJ, Rutigliano RJ, Deb A, Bar-Sagi D, Lim WA (2007) Rewiring cellular morphology pathways with synthetic guanine nucleotide exchange factors. Nature 447:596–600PubMedGoogle Scholar
  122. Yuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I, Schlessinger J (2007) Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell 130:323–334PubMedGoogle Scholar
  123. Zhang R, Shah MV, Yang J, Nyland SB, Liu X, Yun JK, Albert R, Loughran TP Jr (2008) Network model of survival signaling in large granular lymphocyte leukemia. Proc Natl Acad Sci USA 105:16308–16313PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of BiologyUniversity of VirginiaCharlottesvilleUSA
  2. 2.Department of Biomedical EngineeringUniversity of VirginiaCharlottesvilleUSA

Personalised recommendations