Pathway Map Details

Apoptosis and survival_Lymphotoxin-beta receptor signaling



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TRAF2, JNK (MAPK8-10), NF-kB p50/p65, MEKK1 (MAP3K1), c-IAP1, CCL21, CXCL13, LTB, IKK-alpha, VCAM1, TNF-beta, Caspase-3, Caspase-7, NF-kB2 (p52), NF-kB p52/RelB, IKK-beta, IKK-gamma, Cytochrome c, RelB (NF-kB subunit), NF-kB2 (p100), IL-8, Smac/Diablo, Bax, Caspase-9, NIK (MAP3K14), CCL19, Apaf-1, NF-kB1 (p50), RelA (p65 NF-kB subunit), MKK7 (MAP2K7), LTBR(TNFRSF3), ASK1 (MAP3K5), SDF-1, TRAF5, I-kB, MEK4 (MAP2K4), IKK (cat), TRAF3, IL-2, LIGHT(TNFSF14), c-Jun

Description:

Lymphotoxin-beta receptor signaling

Lymphotoxin-beta receptor ( LTBR ), a member of the tumor necrosis factor receptor superfamily, is essential for the development and organization of secondary lymphoid tissue. The LTBR binds specific ligands, such as the membrane form of lymphotoxin heterotrimer, Lymphotoxin-Alpha1Beta2 ( TNF-beta/ LTB heterotrimer); lymphotoxin LT-beta ( LTB ); and homotrimer LIGHT. Expression of TNF-beta/ LTB heterotrimer is restricted to activated hematopoetic cells, whereas LIGHT is expressed both by hematopoetic and non-hematopoetic cells. LTBR activates multiple signaling pathways leading to the expression of adhesion molecules and chemokines, and cell death [1], [2], [3].

LTBR binds to TNF Receptor-Associated Factors ( TRAF2, - 3, and - 5 ) and mediates stimulation of two separate signaling pathways, leading to activation of distinct NF-kB (transcriptional factor) complexes [4], [5].

After triggering expression of LTBR by TNF-beta/ LTB heterotrimer, TRAF2 and TRAF5 activate NIK (NF-kB-Inducing Kinase) [6]. NIK, in turn, phosphorylates and activates IKK-alpha (Inhibitor of KappaB Kinase-Alpha). Both proteins are required for degradation of the NF-kB2 (p52) precursor, NF-kB2 (p100), to yield the mature p52, which heterodimerizes with RelB to form NF-kB p52/RelB heterodimers [7]. NF-kB p52/RelB involves in the expression of chemokines SDF-1, CXCL13, CCL19 and CCL21 [8].

The other NF-kB pathway that leads to the formation of NF-kB p50/p65 heterodimers, involving the Alpha ( IKK-alpha ), Beta ( IKK- beta ) and Gamma ( IKK-gamma ) subunits of the IKK complex, can be turned on after LTBR activation by TNF-beta/ LTB heterotrimer or LTB. IKK -dependent degradation of I-kB (NF-kB inhibitor) and subsequent activation of NF-kB1 (p50) and RelA(p65) is independent of NIK [9], [8]. NF-kB1 and NF-kB p50/p65 regulate a transcription of genes that encode vascular cell adhesion molecule VCAM1, and interleukins IL-2 and IL-8 [10], [11], [12].

LIGHT binding to LTBR also induces JNK/c-Jun activation. All three TRAFs ( TRAF2, - 3, and - 5 ) induce activation of kinases ASK1, MEK4, MKK7 and JNK1/2. TRAF2 also induces MEKK1 / MKK7/ JNK pathway. JNK1/2 kinases phosphorylate and activate transcriptional factor c-Jun that regulates expression of interleukins IL-2 and IL-8 [13], [4], [14], [15].

In addition, LIGHT causes cell death by apoptosis of various tumor cells expressing LTBR. Upon the binding of LIGHT to LTBR, TRAF2 is first recruited to the receptor followed by TRAF3 and c-IAP1 (apoptosis inhibitor 1) recruitment, during which the BIR1 domain of c-IAP1 is cleaved. Thereby c-IAP1, which inhibits activity of caspases by direct interaction with Caspase-9, -7, and -3, is inactivated. The LIGHT - LTBR complex also triggers the mitochondria-mediated apoptosis pathway by an unknown mechanism, which induces the release of Cytochrom c and Smac (second mitochondria-derived activator of caspases) from mitochondria. TRAF3 has been suggested to trigger the release of Smac from mitochondria. The cytosolic Smac is then recruited to the receptor via its interaction with c-IAP1 [5]. Smac causes ubiquitination and the rapid degradation of c-IAP1 [16]. Cytochrom c released from mitochondria promotes the activation of caspase-9 through APAF-1 (apoptotic protease activating factor) [17]. Caspases cascade signaling leads to cell death by apoptosis.

References:

  1. Rooney IA, Butrovich KD, Glass AA, Borboroglu S, Benedict CA, Whitbeck JC, Cohen GH, Eisenberg RJ, Ware CF
    The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. The Journal of biological chemistry 2000 May 12;275(19):14307-15
  2. Gommerman JL, Browning JL
    Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nature reviews. Immunology. 2003 Aug;3(8):642-55
  3. Ware CF
    Network communications: lymphotoxins, LIGHT, and TNF. Annual review of immunology 2005;23:787-819
  4. Chang YH, Hsieh SL, Chen MC, Lin WW
    Lymphotoxin beta receptor induces interleukin 8 gene expression via NF-kappaB and AP-1 activation. Experimental cell research 2002 Aug 15;278(2):166-74
  5. Kuai J, Nickbarg E, Wooters J, Qiu Y, Wang J, Lin LL
    Endogenous association of TRAF2, TRAF3, cIAP1, and Smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis. The Journal of biological chemistry 2003 Apr 18;278(16):14363-9
  6. Song HY, Regnier CH, Kirschning CJ, Goeddel DV, Rothe M
    Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2. Proceedings of the National Academy of Sciences of the United States of America 1997 Sep 2;94(18):9792-6
  7. Richmond A
    Nf-kappa B, chemokine gene transcription and tumour growth. Nature reviews. Immunology. 2002 Sep;2(9):664-74
  8. Muller JR, Siebenlist U
    Lymphotoxin beta receptor induces sequential activation of distinct NF-kappa B factors via separate signaling pathways. The Journal of biological chemistry 2003 Apr 4;278(14):12006-12
  9. Yilmaz ZB, Weih DS, Sivakumar V, Weih F
    RelB is required for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF. The EMBO journal 2003 Jan 2;22(1):121-30
  10. Lai JH, Horvath G, Subleski J, Bruder J, Ghosh P, Tan TH
    RelA is a potent transcriptional activator of the CD28 response element within the interleukin 2 promoter. Molecular and cellular biology 1995 Aug;15(8):4260-71
  11. Chang MM, Harper R, Hyde DM, Wu R
    A novel mechanism of retinoic acid-enhanced interleukin-8 gene expression in airway epithelium. American journal of respiratory cell and molecular biology 2000 Apr;22(4):502-10
  12. Tu Z, Kelley VR, Collins T, Lee FS
    I kappa B kinase is critical for TNF-alpha-induced VCAM1 gene expression in renal tubular epithelial cells. Journal of immunology (Baltimore, Md. : 1950) 2001 Jun 1;166(11):6839-46
  13. Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M
    Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes & development 1999 May 15;13(10):1297-308
  14. Chen MC, Hwang MJ, Chou YC, Chen WH, Cheng G, Nakano H, Luh TY, Mai SC, Hsieh SL
    The role of apoptosis signal-regulating kinase 1 in lymphotoxin-beta receptor-mediated cell death. The Journal of biological chemistry 2003 May 2;278(18):16073-81
  15. Kim YS, Nedospasov SA, Liu ZG
    TRAF2 plays a key, nonredundant role in LIGHT-lymphotoxin beta receptor signaling. Molecular and cellular biology 2005 Mar;25(6):2130-7
  16. Yang QH, Du C
    Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells. The Journal of biological chemistry 2004 Apr 23;279(17):16963-70
  17. Zou H, Li Y, Liu X, Wang X
    An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. The Journal of biological chemistry 1999 Apr 23;274(17):11549-56