TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway (Homo sapiens)

From WikiPathways

Jump to: navigation, search
1Inhibited in skeletal muscle cellsmRNAProteinProliferationLigand(Myotubes)TWEAK Signaling PathwayApoptosisProteosome degradationEnzyme complexInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationProteinDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageRELBNFKB1CYTRAF1NFKB2IKBKBIL6PMAP3K14TRAF3MAPK3HDAC1PTNFRSF12ARAC1TNFSF12TRAF2BIRC2CASP8FADDMAPK1NFKBIBPRIPK1AKT2PTNFSF12TRAF5AKT1CHUKPPNFKBIAPCTNNB1DePCCL5MMP9MAP3K7P MAPK8PMAPK9PRELAPGSK3BPMAPK14TNFSF12PCTNNB1CASP3CCL2CCL5NFKB1RELAPCHUKPDegradationRELBNFKB2CASP8CASP7ProliferationJUNNUCYNUCYNUCYNUCYNUStabilization of MAP3K14Induced activationProteinProtein-protein dissociation(Renal tubular cells)ProliferationProliferation(Endothelial cells)(Endothelial cells)(Osteoblasts)(Tumor cells)AtrophyReceptorTRIM63TNFBIRC3Lysosomal degradationTRAF2TNFTNFTNFRSF1CYEC


TNF related weak inducer of apoptosis (TWEAK) is a small pleiotropic cytokine of the TNF super family and its gene is located at chromosome 17p13.1. TWEAK has been reported to be expressed in tissues that include heart, brain, kidney and also in mononuclear blood cells. The multiple biological activities of TWEAK include stimulation of cell growth and angiogenesis, induction of inflammatory cytokines, and stimulation of apoptosis. It has been shown to be involved in the induction of cellular proliferation in liver cells, osteoblasts, astrocytes, synoviocytes, kidney cells and skeletal muscles. Furthermore, TWEAK plays a substantial role in cellular differentiation in osteoclasts. TWEAK induces glioma cell survival via imparting resistance to cytotoxic agents. It imparts its downstream signaling events by binding to its receptor, FGF inducible 14 protein (Fn14). Two modes of TWEAK-Fn14 (ligand-receptor) interactions have been proposed (i) the ligand dependent interaction which involves the higher concentration of homotrimeric TWEAK, that binds to low concentration of Fn14 in a heterohexameric complex (ii) ligand-independent interaction when the ligand concentration is lower than the receptor concentration which induces the ligand independent interaction. The receptors homotrimerize to activate the downstream events. The signaling cascades reported under TWEAK-Fn14 interactions are the canonical and noncanonical NF-κB pathways and the MAPK pathway. There has been a report on crosstalk between Wnt and TWEAK pathways. In myoblasts the PI3K-AKT module has been reported to be inhibited under TWEAK stimulus. AKT phosprorylation leads to the activation of GSK3β resulting in increase of phospho-GSk3β and active β-catenin1 (CTNNB1) (dephosphorylated) levels. GSK3β and β-catenin1 remain associated in the cytoplasm, phosphorylation of GSK3β leads to the dissociation of β-catenin1 (dephosphorylated) resulting in the nuclear translocation of the protein. Despite of reports on TWEAK binding to other receptors including CD163 and DR3 the downstream events following the binding is yet to be established. The data provided by us would foster enormous avenues for further studies on TWEAK associated proteins and the related disorders such as cancer and autoimmune diseases. The data would enable therapeutic studies by selecting the pathological events and the simultaneous production of blocking agents. Despite the minimal amount of data, ours can also be used in the overlay of various high throughput data enabling pathway analysis and can be accessed by any pathway resource to generate a customized pathway.

Please access this pathway at NetSlim database.

If you use this pathway, please cite Bhattacharjee2012 paper (see below).

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal.

Quality Tags

Ontology Terms



  1. Bhattacharjee M, Raju R, Radhakrishnan A, Nanjappa V, Muthusamy B, Singh K, Kuppusamy D, Lingala BT, Pan A, Mathur PP, Harsha HC, Prasad TS, Atkins GJ, Pandey A, Chatterjee A; ''A Bioinformatics Resource for TWEAK-Fn14 Signaling Pathway.''; J Signal Transduct, 2012 PubMed Europe PMC Scholia


View all...
105837view23:10, 15 August 2019KhanspersModified description
96646view10:18, 25 March 2018EgonwModified description
96645view10:18, 25 March 2018EgonwAdded the article (in prep at the time).
89910view13:24, 6 October 2016EgonwModified description
85741view08:56, 9 June 2016EveloModified title
84527view09:32, 29 February 2016MirellaKalafatiUpdate gene identifier to Uniprot-TREMBL
79948view10:40, 28 April 2015Zariannotated MAP3K14 and CHUK
78525view10:29, 7 January 2015MaintBotadded missing graphIds
72733view01:45, 4 December 2013AlexanderPicoRemoved erroneous (leftover?) SHH datanode hidden off canvas
71694view19:42, 17 October 2013MaintBotremoved data source from nodes without identifier
70106view18:57, 12 July 2013MaintBotupdated to 2013 schema
67729view11:55, 26 June 2013DdiglesOntology Term : 'tumor necrosis factor superfamily mediated signaling pathway' added !
48448view15:54, 24 May 2012NetPathModified description
47075view00:05, 15 March 2012KhanspersModified categories
46204view22:30, 3 January 2012KhanspersUpdating gpml
46066view19:53, 12 December 2011KhanspersUpdating gpml
44633view18:21, 22 September 2011KhanspersNew pathway

External references


View all...
NameTypeDatabase referenceComment
MAPK8Protein5599 (Entrez Gene)
AKT1Protein207 (Entrez Gene)
AKT2Protein208 (Entrez Gene)
ApoptosisPathwayWP254 (WikiPathways)
BIRC2Protein329 (Entrez Gene)
BIRC3Protein330 (Entrez Gene)
CASP3ProteinP42574 (Uniprot-TrEMBL)
CASP7Protein840 (Entrez Gene)
CASP8Protein841 (Entrez Gene)
CCL2Rna6347 (Entrez Gene)
CCL5Rna6352 (Entrez Gene)
CHUKProtein1147 (Entrez Gene)
CTNNB1Protein1499 (Entrez Gene)
FADDProtein8772 (Entrez Gene)
GSK3BProtein2932 (Entrez Gene)
HDAC1Protein3065 (Entrez Gene)
IKBKBProtein3551 (Entrez Gene)
IL6Rna3569 (Entrez Gene)
JUNProtein3725 (Entrez Gene)
MAP3K14ProteinENSG00000006062 (Ensembl)
MAP3K7Protein6885 (Entrez Gene)
MAPK14Protein1432 (Entrez Gene)
MAPK1Protein5594 (Entrez Gene)
MAPK3Protein5595 (Entrez Gene)
MAPK9Protein5601 (Entrez Gene)
MMP9Rna4318 (Entrez Gene)
NFKB1Protein4790 (Entrez Gene)
NFKB2Protein4791 (Entrez Gene)
NFKBIAProtein4792 (Entrez Gene)
NFKBIBProtein4793 (Entrez Gene)
ProteinProtein5894 (Entrez Gene)
Proteosome degradationPathwayWP183 (WikiPathways)
RAC1Protein5879 (Entrez Gene)
RELAProtein5970 (Entrez Gene)
RELBProtein5971 (Entrez Gene)
RIPK1Protein8737 (Entrez Gene)
TNFProtein7124 (Entrez Gene)
TNFRSF12AProtein51330 (Entrez Gene)
TNFRSF1Protein51330 (Entrez Gene)
TNFSF12Protein8742 (Entrez Gene)
TRAF1Protein7185 (Entrez Gene)
TRAF2Protein7186 (Entrez Gene)
TRAF3Protein7187 (Entrez Gene)
TRAF5Protein7188 (Entrez Gene)
TRIM63Protein84676 (Entrez Gene)

Annotated Interactions

No annotated interactions

Personal tools