TNFR2 non-canonical NF-kB pathway (Homo sapiens)

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9, 14, 16, 17, 20...21, 22, 43, 50272, 3125, 3425, 497, 16, 24, 28, 363, 4725, 40, 491, 13, 30, 37, 45...25, 3319, 39102, 3125, 335, 23, 35, 44, 4646, 26, 291225, 498, 38cytosolcytosolcytosolMAP3K14TNFSF11 CD40-1 TNFRSF1BTNFRSF13C TRAF3:NIKlymphotoxin,TNFSF14trimerCD40:CD40Ltrimer:cIAP1,2:TRAF2:TRAF3:NIKPSMA6 LTBR MAP3K14 cIAP1,2:TRAF2:TRAF3:NIKPSMA4 CD40LG(1-261) BIRC2 TRAF2 TNFSF12 TRAF2 CD40-1 MAP3K14 PSMC6 TNFRSF11A sTNFSF11 LTBRTNFSF14 sTNFSF11 TNFRSF11A TNFSF14 TNFSF14 BIRC2 TNF(1-233) TRAF2 CD40-1 CD40LG(1-261) MAP3K14 K63polyUbTNFSF11 3xLTBR:lymphotoxin,TNFSF14 trimer:cIAP1,2:TRAF2:TRAF3:NIKTNFSF14 TNFRSF13C TNFSF12 TNFSF:TNFRSFheterotrimer:TRAF2:K63polyUb-cIAP1,2:K48polyUb-TRAF3:NIKlymphotoxin (LA) sTNFSF11 LTBR PSMD1 sBAFF K63polyUb-BIRC3 sTNFSF12 PSME3 PSMB11 TRAF3 SHFM1 TNFRSF1B TNFRSF12ATNFRSF1B 3xFn14:TWEAK:cIAP1,2:TRAF2:TRAF3:NIKlymphotoxin (LA) TNFSF11 TNFSF12 PSMB6 TRAF3 TNFRSF1B TNFSF11 sTNFSF12 TNFRSF13C PSME2 LTBR lymphotoxin (LA) TNFRSF13CTRAF1:TRAF2:K63polyUb-cIAP1,2BIRC3 TNFRSF12A RANKL,sRANKL trimerTNFRSF12A PSMD8 sBAFF TNF(1-233) trimersBAFF CD40-1 TNFRSF11A PSMC2 K63polyUb-BIRC3 TNFRSF12A TNFRSF13C BIRC3 TNF(1-233) PSMB2 TNFSF11 LTBR BIRC2 sTNFSF12 TNFRSF11A TNFRSF12A TNFSF12 TNFRSF13C TRAF3 TNF(1-233) sTNFSF12 PSMB5 TRAF3 TRAF2 CD40:CD40L trimerTRAF3 PSMA8 TRAF3 TRAF2 PSMA1 K48polyUb-NIKsTWEAK,TWEAKhomotrimersTNFSF11 K48polyUbTNFRSF11A TRAF2 sTNFSF11 PSMA3 PSMB7 3xBAFFR:BAFFtrimer:TRAF3:NIKK63polyUb-BIRC2 sTNFSF12 K63polyUb-BIRC3 K63polyUb-BIRC2 PSMD13 lymphotoxin (LA) MAP3K14 PSMD4 Non-canonical NF-kBinitiating TNFRSFmemebersTRAF3 CD40 trimerPSMA5 MAP3K14 sTNFSF12 TNF(1-233) PSMD3 TNFRSF1B lymphotoxin (LA) sBAFF TNFSF14 TNFA:TNFR2heterotrimer:cIAP1,2:TRAF2:TRAF3:NIKMAP3K14 PSME4 TNFA:TNFR2,BAFF:BAFFR,TWEAK:Fn14,Lymphotoxin:LTBR,RANKL:RANK,CD40L:CD40TNFSF12 LTBR BIRC2 CD40-1 PSMC3 K48polyUbTNFSF12 sBAFF lymphotoxin (LA) 3xFN14:sTWEAK,TWEAKhomotrimersTNFSF11 PSMD5 TRAF3 TRAF2:cIAP1,2RANK:RANKL,sRANKLtrimerTNFRSF12A TRAF3 CD40LG(1-261) CD40-1 TNFs bind theirphysiologicalreceptorsPSMD9 PSMA7 PSMB3 BIRC3 sTNFSF11 TNFRSF1B BIRC3 TRAF2 TNF(1-233) PSMD14 TNFRSF11A TNFRSF11AsBAFF CD40-1 K48polyUb-TRAF3 CD40LG(1-261) TNFRSF1B TRAF3 PSMD10 TNFRSF13C BIRC2 PSMF1 CD40LG trimerTNFSF11 TNFSF12 BIRC3 PSMD6 sTNFSF12 TNFSF11 3xRANK:RANKL,sRANKLtrimer:cIAP1,2:TRAF2:TRAF3:NIKPSMD2 MAP3K14 TNF(1-233) TRAF2 BIRC3 BIRC2 LTBR MAP3K14 PSMB10 CD40LG(1-261) TNFRSF12A MAP3K14 PSMD7 PSMA2 BIRC3 sBAFF TRAF2 PSMB9 TRAF2 3xLTBR:lymphotoxin,TNFSF14 trimerCD40LG(1-261) MAP3K14 TNFRSF1B sBAFF trimerTNF(1-233) PSME1 BIRC2 BIRC3 TRAF3TNFSF14 BIRC2 PSMB1 BIRC2 TNFSF14 3xRANK:RANKL,sRANKLtrimerLTBR:lymphotoxin,TNFSF14 trimerCD40LG(1-261) TNF(1-233) PSMB4 lymphotoxin (LA) MAP3K14 LTBR 3xBAFFR:BAFF trimer26S proteasomeBIRC3 NIK-->noncanonicalNF-kB signalingTRAF2 TRAF2 PSMC1 TNFA trimer:TNFR2trimerK63polyUb-BIRC2 PSMB8 sTNFSF11 TNFA trimer:TNFR2sTNFSF11 TNFRSF11A lymphotoxin (LA) TNFSF14 PSMC4 TNFSF:TNFRSFheterotrimer:K63polyUb-cIAP1,2:TRAF2:TRAF3:NIKPSMD11 PSMC5 PSMD12 9, 17, 32, 42111811, 4115


Tumor necrosis factor-alpha (TNFA) exerts a wide range of biological effects through TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Under normal physiological conditions TNFR2 exhibits more restricted expression, being found on certain subpopulation of immune cells and few other cell types (Grell et al. 1995 ). TNFR1 mediated signalling pathways have been very well characterized but, TNFR2 has been much less well studied. TNFR1 upon activation by TNFA activates apoptosis through two pathways, involving the adaptor proteins TNFR1-associated death domain (TRADD) and fas-associated death domain (FADD). In contrast, TNFR2 signalling especially in highly activated T cells, induces cell survival pathways that can result in cell proliferation by activating transcription factor NF-kB (nuclear factor-kB) via the alternative non-canonical route. TNFR2 signalling seems to play an important role, in particular for the function of regulatory T cells. It offers protective roles in several disorders, including autoimmune diseases, heart diseases, demyelinating and neurodegenerative disorders and infectious diseases (Faustman & Davis 2010).
Activation of the non-canonical pathway by TNFR2 is mediated through a signalling complex that includes TNF receptor-associated factor (TRAF2 and TRAF3), cellular inhibitor of apoptosis (cIAP1 and cIAP2), and NF-kB-inducing kinase (NIK). In this complex TRAF3 functions as a bridging factor between the cIAP1/2:TRAF2 complex and NIK. In resting cells cIAP1/2 in the signalling complex mediates K48-linked polyubiquitination of NIK and subsequent proteasomal degradation making NIK levels invisible. Upon TNFR2 stimulation, TRAF2 is recruited to the intracellular TRAF binding motif and this also indirectly recruits TRAF1 and cIAP1/2, as well as TRAF3 and NIK which are already bound to TRAF2 in unstimulated cells. TRAF2 mediates K63-linked ubiquitination of cIAP1/2 and this in turn mediates cIAP dependent K48-linked ubiquitination of TRAF3 leading to the proteasome-dependent degradation of the latter. As TRAF3 is degraded, NIK can no longer interact with TRAF1/2:cIAP complex. As a result NIK concentration in the cytosol increases and NIK gets stabilised and activated. Activated NIK phosphorylates IKKalpha, which in turn phosphorylates p100 (NFkB2) subunit. Phosphorylated p100 is also ubiquitinated by the SCF-beta-TRCP ubiquitin ligase complex and is subsequently processed by the proteaseome to p52, which is a transcriptionally competent NF-kB subunit in conjunction with RelB (Petrus et al. 2011, Sun 2011, Vallabhapurapu & Karin 2009). View original pathway at:Reactome.


Pathway is converted from Reactome ID: 5668541
Reactome version: 66
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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101609view11:47, 1 November 2018ReactomeTeamreactome version 66
101146view21:33, 31 October 2018ReactomeTeamreactome version 65
100674view20:06, 31 October 2018ReactomeTeamreactome version 64
100224view16:52, 31 October 2018ReactomeTeamreactome version 63
99775view15:17, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99332view12:47, 31 October 2018ReactomeTeamreactome version 62
93856view13:41, 16 August 2017ReactomeTeamreactome version 61
93419view11:23, 9 August 2017ReactomeTeamreactome version 61
88404view11:39, 5 August 2016FehrhartOntology Term : 'tumor necrosis factor mediated signaling pathway' added !
86507view09:19, 11 July 2016ReactomeTeamreactome version 56
83401view11:08, 18 November 2015ReactomeTeamVersion54
81598view13:08, 21 August 2015ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
26S proteasomeComplexR-HSA-68819 (Reactome)
3xBAFFR:BAFF trimer:TRAF3:NIKComplexR-HSA-5676561 (Reactome)
3xBAFFR:BAFF trimerComplexR-HSA-5676540 (Reactome)
3xFN14:sTWEAK,TWEAK homotrimerComplexR-HSA-5675977 (Reactome)
3xFn14:TWEAK:cIAP1,2:TRAF2:TRAF3:NIKComplexR-HSA-5676555 (Reactome)
3xLTBR:lymphotoxin,TNFSF14 trimer:cIAP1,2:TRAF2:TRAF3:NIKComplexR-HSA-5676558 (Reactome)
3xLTBR:lymphotoxin,TNFSF14 trimerComplexR-HSA-5676545 (Reactome)
3xRANK:RANKL,sRANKL trimer:cIAP1,2:TRAF2:TRAF3:NIKComplexR-HSA-5676557 (Reactome)
3xRANK:RANKL,sRANKL trimerComplexR-HSA-5676546 (Reactome)
BIRC2 ProteinQ13490 (Uniprot-TrEMBL)
BIRC3 ProteinQ13489 (Uniprot-TrEMBL)
CD40 trimerComplexR-HSA-5672850 (Reactome)
CD40-1 ProteinP25942-1 (Uniprot-TrEMBL)
CD40:CD40L trimer:cIAP1,2:TRAF2:TRAF3:NIKComplexR-HSA-5676556 (Reactome)
CD40:CD40L trimerComplexR-HSA-199402 (Reactome)
CD40LG trimerComplexR-HSA-5672851 (Reactome)
CD40LG(1-261) ProteinP29965 (Uniprot-TrEMBL)
K48polyUb-NIKProteinQ99558 (Uniprot-TrEMBL)
K48polyUb-TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
K48polyUbR-HSA-912740 (Reactome)
K63polyUb-BIRC2 ProteinQ13490 (Uniprot-TrEMBL)
K63polyUb-BIRC3 ProteinQ13489 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
LTBR ProteinP36941 (Uniprot-TrEMBL)
LTBR:lymphotoxin,TNFSF14 trimerComplexR-HSA-5668802 (Reactome)
LTBRProteinP36941 (Uniprot-TrEMBL)
MAP3K14 ProteinQ99558 (Uniprot-TrEMBL)
MAP3K14ProteinQ99558 (Uniprot-TrEMBL)
NIK-->noncanonical NF-kB signalingPathwayR-HSA-5676590 (Reactome) In addition to the activation of canonical NF-kB subunits, activation of SYK pathway by Dectin-1 leads to the induction of the non-canonical NF-kB pathway, which mediates the nuclear translocation of RELB-p52 dimers through the successive activation of NF-kB-inducing kinase (NIK) and IkB kinase-alpha (IKKa) (Geijtenbeek & Gringhuis 2009, Gringhuis et al. 2009). Noncanonical activity tends to build more slowly and remain sustained several hours longer than does the activation of canonical NF-kB. The noncanonical NF-kB pathway is characterized by the post-translational processing of NFKB2 (Nuclear factor NF-kappa-B) p100 subunit to the mature p52 subunit. This subsequently leads to nuclear translocation of p52:RELB (Transcription factor RelB) complexes to induce cytokine expression of some genes (C-C motif chemokine 17 (CCL17) and CCL22) and transcriptional repression of others (IL12B) (Gringhuis et al. 2009, Geijtenbeek & Gringhuis 2009, Plato et al. 2013).
Non-canonical NF-kB

initiating TNFRSF

ComplexR-HSA-5676554 (Reactome)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
RANK:RANKL,sRANKL trimerComplexR-HSA-5676553 (Reactome)
RANKL,sRANKL trimerComplexR-HSA-5676542 (Reactome)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
TNF(1-233) ProteinP01375 (Uniprot-TrEMBL)
TNF(1-233) trimerComplexR-HSA-3371351 (Reactome)
TNFA trimer:TNFR2 trimerComplexR-HSA-5668423 (Reactome)
TNFA trimer:TNFR2ComplexR-HSA-5668502 (Reactome)
TNFA:TNFR2 heterotrimer:cIAP1,2:TRAF2:TRAF3:NIKComplexR-HSA-5668447 (Reactome)
TNFA:TNFR2,BAFF:BAFFR,TWEAK:Fn14,Lymphotoxin:LTBR,RANKL:RANK,CD40L:CD40ComplexR-HSA-5676550 (Reactome)
TNFRSF11A ProteinQ9Y6Q6 (Uniprot-TrEMBL)
TNFRSF11AProteinQ9Y6Q6 (Uniprot-TrEMBL)
TNFRSF12A ProteinQ9NP84 (Uniprot-TrEMBL)
TNFRSF12AProteinQ9NP84 (Uniprot-TrEMBL)
TNFRSF13C ProteinQ96RJ3 (Uniprot-TrEMBL)
TNFRSF13CProteinQ96RJ3 (Uniprot-TrEMBL)
TNFRSF1B ProteinP20333 (Uniprot-TrEMBL)
TNFRSF1BProteinP20333 (Uniprot-TrEMBL)
TNFSF11 ProteinO14788 (Uniprot-TrEMBL)
TNFSF12 ProteinO43508 (Uniprot-TrEMBL)
TNFSF14 ProteinO43557 (Uniprot-TrEMBL)
TNFSF:TNFRSF heterotrimer:K63polyUb-cIAP1,2:TRAF2:TRAF3:NIKComplexR-HSA-5668433 (Reactome)
TNFSF:TNFRSF heterotrimer:TRAF2:K63polyUb-cIAP1,2:K48polyUb-TRAF3:NIKComplexR-HSA-5668442 (Reactome)
TNFs bind their


PathwayR-HSA-5669034 (Reactome) Members of the tumour necrosis factor superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) have crucial roles in both innate and adaptive immunity. These members are implicated in various acquired or genetic human diseases, ranging from septic shock to autoimmune disorders, allograft rejection and cancer (So et al. 2006).
TRAF1:TRAF2:K63polyUb-cIAP1,2ComplexR-HSA-5668475 (Reactome)
TRAF2 ProteinQ12933 (Uniprot-TrEMBL)
TRAF2:cIAP1,2ComplexR-HSA-5668489 (Reactome)
TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
TRAF3:NIKComplexR-HSA-5668511 (Reactome)
TRAF3ProteinQ13114 (Uniprot-TrEMBL)
cIAP1,2:TRAF2:TRAF3:NIKComplexR-HSA-5668435 (Reactome)
lymphotoxin (LA) R-HSA-5676543 (Reactome)
lymphotoxin,TNFSF14 trimerComplexR-HSA-5668763 (Reactome)
sBAFF ProteinQ9Y275 (Uniprot-TrEMBL)
sBAFF trimerComplexR-HSA-5676548 (Reactome)
sTNFSF11 ProteinO14788 (Uniprot-TrEMBL)
sTNFSF12 ProteinO43508 (Uniprot-TrEMBL)
sTWEAK,TWEAK homotrimersComplexR-HSA-5675962 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisR-HSA-5668481 (Reactome)
26S proteasomemim-catalysisR-HSA-5668520 (Reactome)
3xBAFFR:BAFF trimer:TRAF3:NIKArrowR-HSA-5676596 (Reactome)
3xBAFFR:BAFF trimerArrowR-HSA-5676599 (Reactome)
3xBAFFR:BAFF trimerR-HSA-5676596 (Reactome)
3xFN14:sTWEAK,TWEAK homotrimerArrowR-HSA-5669023 (Reactome)
3xFN14:sTWEAK,TWEAK homotrimerR-HSA-5676598 (Reactome)
3xFn14:TWEAK:cIAP1,2:TRAF2:TRAF3:NIKArrowR-HSA-5676598 (Reactome)
3xLTBR:lymphotoxin,TNFSF14 trimer:cIAP1,2:TRAF2:TRAF3:NIKArrowR-HSA-5676593 (Reactome)
3xLTBR:lymphotoxin,TNFSF14 trimerArrowR-HSA-5676591 (Reactome)
3xLTBR:lymphotoxin,TNFSF14 trimerR-HSA-5676593 (Reactome)
3xRANK:RANKL,sRANKL trimer:cIAP1,2:TRAF2:TRAF3:NIKArrowR-HSA-5676595 (Reactome)
3xRANK:RANKL,sRANKL trimerArrowR-HSA-5676592 (Reactome)
3xRANK:RANKL,sRANKL trimerR-HSA-5676595 (Reactome)
CD40 trimerR-HSA-199404 (Reactome)
CD40:CD40L trimer:cIAP1,2:TRAF2:TRAF3:NIKArrowR-HSA-5676597 (Reactome)
CD40:CD40L trimerArrowR-HSA-199404 (Reactome)
CD40:CD40L trimerR-HSA-5676597 (Reactome)
CD40LG trimerR-HSA-199404 (Reactome)
K48polyUb-NIKArrowR-HSA-5668534 (Reactome)
K48polyUb-NIKR-HSA-5668520 (Reactome)
K48polyUbR-HSA-5668454 (Reactome)
K48polyUbR-HSA-5668534 (Reactome)
K63polyUbR-HSA-5668414 (Reactome)
LTBR:lymphotoxin,TNFSF14 trimerArrowR-HSA-5668789 (Reactome)
LTBR:lymphotoxin,TNFSF14 trimerR-HSA-5676591 (Reactome)
LTBRR-HSA-5668789 (Reactome)
LTBRR-HSA-5676591 (Reactome)
MAP3K14ArrowR-HSA-5668481 (Reactome)
Non-canonical NF-kB

initiating TNFRSF

R-HSA-5668414 (Reactome)
Non-canonical NF-kB

initiating TNFRSF

mim-catalysisR-HSA-5668414 (Reactome)
R-HSA-199404 (Reactome) CD40 is a member of the Tumour Necrosis Factor receptor family and its ligand CD40L is a type II transmembrane protein of the TNF superfamily. The latter is expressed preferentially on T-cells and platelets. In the immune system, CD40-CD40L interaction affects some key processes such as immune cell activation, differentiation, proliferation, and apoptosis. CD40-CD40L interaction also upregulates costimulatory molecules (ICAM-1, VCAM-1, E-selectin, LFA-3, B7.1, B7.2, class II MHC, and CD40 itself).
R-HSA-5668404 (Reactome) Tumor necrosis factor alpha (TNFA) exists in two biologically active forms, a transmembrane TNF-alpha (tmTNFA) and secretory TNF-alpha (sTNFA). tmTNFA is expressed as a functional 26kDa homotrimer transmembrane protein, which can be cleaved by a metalloproteinase TNFA-converting enzyme (TACE or ADAM17) to release the extracellular C-terminal portion with 17kDa, sTNFA. Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B or hereafter referred as TNFR2) preferentially binds with membrane integrated TNFA (Grell et al. 1995) and can activate the noncanonical NF-kB pathway (Rauert et al. 2010) as well as canonical NF-kB pathway (Marchetti et al. 2004).
R-HSA-5668414 (Reactome) Following recruitment to receptor, TRAF2 mediates K63-linked polyubiquitination of cIAP1 and cIAP2. In addition to being an adaptor that recruits cIAP1/2 and TRAF3 to the receptor TRAF2 is also an E3 that activates cIAP1/2, through their K63-linked ubiquitination. This K63-linked ubiquitination stimulates the K48-ubiquitin ligase function of cIAP1/2 and may impose a change in the substrate specificity of cIAP1/2. Thus, rather than ubiquitinating NIK, cIAP1/2 ubiquitinates TRAF3 leading to its degradation (Vallabhapurapu et al. 2008, Wallach & Kovalenko 2008).
R-HSA-5668417 (Reactome) Tumor necrosis factor receptor 2 (TNFR2) signalling starts with recruitment of the adaptor protein TNF receptor-associated factor 2 (TRAF2) to the intracellular TRAF-binding motif and consequently to indirect recruitment of the TRAF2 associated proteins cellular inhibitors of apoptosis 1 and 2 (cIAP1 and cIAP2), along with a complex of TRAF3 and NF-kB-inducing kinase (NIK) which already interact with TRAF2 in unstimulated cells (Song & Donner. 1994, Rothe et al. 1995, Rothe et al. 1994). In resting cells usually NIK is targeted for ubiquitination and proteasomal degradation however in stimulated cells NIK escapes the ubiquitination by the cIAP1,2:TRAF2::TRAF3 complex due to rapid degradation of TRAF3.
R-HSA-5668454 (Reactome) cIAP1,2 targets NIK for ubiquitination and degradation under unstimulated conditions but redirects its destructive action towards TRAF3 in response to receptor signals. K63polyUb-cIAP1,2 catalyses K48-linked polyubiquitination of TRAF3 leading to signal-induced TARF3 degradation.
R-HSA-5668467 (Reactome) TNF receptor-associated factor 2 (TNFR2) undergoes trimerization upon binding of transmembrane bound TNFA (tmTNFA) trimers, which leads to recruitment of TRAF2 to the intracellular TRAF-binding motif of TNFR2.
R-HSA-5668481 (Reactome) K48-linked ubiquitination of TRAF3 further leads to its proteasome-dependent degradation. The resultant degradation of TRAF3 releases NIK from the cIAPs ubiquitin-ligase complex. NIK can escape from ubiquitination and subsequent degradation resulting in accumulation in the cytosol (Sas et al. 2012).
R-HSA-5668520 (Reactome) Polyubiquitinated NIK is targeted for proteasomal degradation and as a consequence the NIK levels are invisible and thus prevent non-canonical NF-kB activation.
R-HSA-5668534 (Reactome) TNF receptor-associated factor 2 (TRAF2) and cellular inhibitors of apoptosis 1 and 2 (cIAP1,2) are both RING-containing ubiquitin protein ligase (E3), and the interplay between these two protein families and other molecules in the receptor complex is critical in the propagation of downstream signals (Rothe et al. 1995, Yang et al., 2000). cIAP1,2 initiates proteasomal degradation of NIK by mediating its K48-linked ubiquitination (K48-(Ub)n).
R-HSA-5668543 (Reactome) Mitogen-activated protein kinase kinase kinase 14 (MAP3K14 also named as NIK) is a central signalling component of the non-canonical pathway which integrates signals from TNFR2 and activates IkB kinase-alpha (IkBA) for triggering p100 phosphorylation and processing (Sun 2011). A tight control of NIK stability is essential to achieve controlled activation of the noncanonical NF-kB signalling upon TNFR2 activation. In unstimulated cells the level of NIK protein is extremely low, which is due to constant degradation by a ubiquitination-dependent mechanism (Liao et al. 2004). Proteasomal degradation of NIK occurs on assembly of a regulatory complex through TRAF3 complexed with NIK and TRAF2 which exists in a preassembled complex with cellular Inhibitor of apoptosis 1 (cIAP1) and cIAP2 (cIAP1,2:TRAF2::TRAF3:NIK). The c-IAPs do not directly contact TNFR2, but rather associate with TRAF2 through their N-terminal BIR motif-comprising domain (Rothe et al. 1995, Shu et al. 1996). TRAF3 functions as a bridging factor between cIAP1/2-TRAF2 E3 complex and NIK enabling cIAP to mediate K48 linked ubiquitination of NIK (Zarnegar et al. 2008, Vallabhapurapu et al. 2008, Li et al. 2004).
R-HSA-5668789 (Reactome) Lymphotoxin-beta receptor (LTBR or TNFR3) is a tumor necrosis factor receptor superfamily (TNFRSF) member that is expressed in lymphoid stromal and epithelial cells and binds two members of the TNFSF, the lymphotoxin alpha/beta (LTA/B) heterotrimers, as well as homotrimeric TNFSF14 (LIGHT) (Rooney et al. 2000, Aggarwal 2003). Both ligands are cytokines produced by activated lymphocytes that plays an important role in the inflammatory and immunologic response. LTA is a product of stimulated T cells and can help elicit cytotoxic effects on cancer cells (Stopfer et al. 2004, Crowe et al. 1994, Mauri et al. 1998, Ware et al. 1992). LTBR (TNFR3) signalling mediates responses controlling cellular differentiation, development and maintenance of peripheral lymphoid organs, dendritic cell homeostasis, hepatic regeneration, interferon responses to pathogens, and death of mucosal derived carcinomas (Norris & Ware 2007, Schneider et al. 2004).
R-HSA-5669023 (Reactome) The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK or TNFSF12) is a member of the TNF superfamily (TNFSF) that contribute to acute kidney injury (AKI) and chronic kidney disorder (CKD), where it has been shown to regulate cell death, inflammation, and fibrosis through activation of the TWEAK receptor fibroblast growth factor-inducible 14 (FN14 or TNFRSF12A). FN14 (TNFRSF12A) is a type I transmembrane and the smallest member of the TNF receptor super family. TWEAK mediates NF-kappaB activation to promote angiogenesis and the proliferation of endothelial cells via its binding to FN14 (TNFSF12A) (Poveda et al. 2013, Lynch et al. 1999, Wiley et al. 2001, Wiley & Winkles 2003). Both membrane bound and soluble forms of TWEAK form homotrimers and have been shown to be able to bind to three monomers of receptor FN14 and trigger signalling (Roos et al. 2010).
R-HSA-5676589 (Reactome) Receptor activator of the NF-kB (RANK also known as TNFRSF11A) is a type I transmembrane protein expressed on osteoclast precursors, dendritic cells and activated B cells, and in general RANK signalling promotes cell survival and differentiation. RANK and its ligand RANKL (TNFSF11) are key regulators of bone remodeling, and they are essential for the development and activation of osteoclasts (Nakagawa et al. 1998). RANK/RANKL interaction also regulates important immune functions, such as dendritic cell survival and lymphoid organogenesis (Sun 2011, Theill et al. 2002). RANKL (also known as TNFSF11) is a type II transmembrane protein, primarily expressed on the surface of activated T-cells, bone marrow stromal cells, and osteoblasts. Soluble form of RANKL (sRANKL) that arise from either proteolytic cleavage or alternative splicing have also been observed. Both the membrane bound and soluble forms of RANKL are assembled into functional homotrimers like other members of the TNFSF (Liu et al. 2010).
R-HSA-5676591 (Reactome) Homotrimeric TNF superfamily (TNFSF) ligands signal by inducing trimerization or higher order oligomerization of their cognate receptors. Upon binding its trivalent ligands lymphotoxin and LIGHT (TNFSF14), lymphotoxin-beta receptor (LTBR/TNFR3) undergoes ordered aggregation or clustering. Heterotrimeric lymphotoxin alpha1beta2 (LTA1B2) induces dimerization rather than trimerization of the LTBR. The crystal structure of this complex reveals that dimerization of LTBA is necessary and sufficient for signal transduction (Sudhamsu et al. 2013). Upon oligomerization, LTBR activates multiple signaling pathways including transcriptional factor NF kappa B (NF-kB), c-Jun N-terminal kinase (JNK), and cell death.
R-HSA-5676592 (Reactome) The binding of RANKL trimer to RANK causes the trimerization of the receptor, which activates the signalling pathway and results in osteogenesis from progenitor cells and the activation of mature osteoclasts (Liu et al. 2010)
R-HSA-5676593 (Reactome) After clustering or dimerisation lymphotoxin-beta receptor (LTBR) initiates signal transduction by recruiting different TNF receptor-associated factor (TRAF) adaptors to the cytoplasmic domain. LTBR directly binds to several TRAFs, including TRAF2 and TRAF3 through its TRAF-interacting peptide motif (VanArsdale et al. 1997, Nakano et al. 1996, Sanjo et al. 2010).
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14 also named as NIK) is a central signalling component of the non-canonical pathway and a tight control of NIK activation by TRAFs is essential to achieve controlled activation of the noncanonical NF-kB signalling. In unstimulated cells ubiquitin:NIK E3 ligase complex catalyses K48-linked ubiquitination of NIK, leading to constitutive NIK degradation. The ubiquitin:NIK E3 ligase is a multisubunit complex comprised of TRAF3 and TRAF2 in association with cellular inhibitors of apoptosis (cIAP1,2). In the activated state the TRAF2:cIAP1,2:TRAF3:NIK complex is recruited to the receptor upon ligand binding whereupon TRAF2-mediated, K63-linked ubiquitination of cIAP1,2 switches its K48 ubiquitin ligase activity from NIK to TRAF3. The resultant TRAF3 degradation destabilizes the TRAF-cIAP complex, so allowing the accumulation of newly synthesised NIK (Razani et al. 2011, Sun 2011).
R-HSA-5676595 (Reactome) Upon activation, RANK on osteoclasts sends signals into the cells by recruiting adapter proteins like tumor necrosis factor receptor-associated factors (TRAFs) and mediates activation of noncanonical NF-kB signalling pathways (Novack et al. 2003, Chaisson ML et al. 2004, Vaira et al. 2007). RANK interacts with TRAFs 1, 2, 3, 5, and 6 however, only TRAF2, TRAF5, and TRAF6 are functionally competent to activate signaling pathways (Kanazawa & Kudi 2004, Galibert et al. 1998, Darnay et al.1999, Darnay et al. 2000).
R-HSA-5676596 (Reactome) In the absence of BAFFR (TNFSF13C) ligation to BAFF (TNFSF13B) ligand, NFkB-inducing kinase (NIK) forms a complex with TNF receptor associated factor 3 (TRAF3) and TRAF2 which exists in a preassembled complex with cellular Inhibitor of apoptosis 1 (cIAP1) and cIAP2 in the cytosol. cIAP1/2 targets NIK for degradation by ubiquitylation, there by inhibiting non-canonical NFkB pathway (Vallabhapurapu et al. 2008, Zarnegar et al. 2008). Upon BAFF trimer binding to BAFFR, TRAF3 but not TRAF2 is recruited to the receptor via a 'PVPAT' binding site. This unique feature of BAFFR to recruit TRAF3 instead of TRAF2 is primarily due to its possession of an atypical TRAF-binding sequence (Morrison et al 2005). Following recruitment to BAFFR, TRAF3 undergoes proteasomal degradation, a process which requires TRAF2 and cIAP1/2.
R-HSA-5676597 (Reactome) After its ligation with CD40 ligand (CD40L), CD40 is activated and triggers direct recruitment of multiple TRAF proteins and initiate non-canonical NF-kB pathway. TRAF1, TRAF2, TRAF3, and TRAF6, but not TRAF4 or TRAF5, shown to bind directly to the CD40 cytoplasmic domain (Pullen et al. 1998). TRAF2 is part of the regulatory complex which includes cellular inhibitor of apoptosis (cIAP) 1 and 2 and which in turn interacts with TRAF3 and NFkB-inducing kinase (NIK). In unstimulated cells this regulatory complex acts as a negative regulator of non-canonical NFkB pathway by constantly degrading NIK, whereas up on recruitment to CD40 this complex leads to accumulation of NIK (Elgueta et al. 2009, Schonbeck & Libby 2001).
R-HSA-5676598 (Reactome) The FN14 (TNFRSF12A) intracellular domain lacks the characteristic death domain of TNF receptor superfamily (TNFRSF) but contains TNFR-associated factor (TRAF) binding sites. Upon TWEAK binding, FN14 recruits TRAF2 and TRAF3 to activate both canonical and non-canonical nuclear factor-kappa B (NF-kB) pathway (Brown et al. 2003, Saitoh et al. 2003, Sanz et al. 2010). NF-kB activation plays a key role in TWEAK-elicited inflammatory responses. TWEAK/FN14 binding induces NIK activation through targeting the degradation of TRAF2/cellular inhibitor of apoptosis (cIAP) 1 and 2 complex (Vince et al. 2008). TWEAK activation of the non-canonical NF-kB pathways promotes inflammatory responses in tubular cells. In cultured renal tubular cells TWEAK increases nuclear RelB/p52 accumulation, RelB and p52 DNA-binding activity, and NIK- and RelB-dependent CCL21 and CCL19 expression (Poveda et al. 2010).
R-HSA-5676599 (Reactome) B cell activating factor of the TNF family (BAFF, also known as TNFSF13B) is a type II transmembrane protein that binds and predominantly activates its receptor BAFFR (TNFRSF13C) to transmit survival and growth signals to B cells (Li et al. 2008). BAFF is the most critical soluble factor for peripheral B-cell maturation and survival. BAFF is expressed by T cells, macrophages and dendritic cells, but not B cells. BAFF is primarily synthesised as membrane-bound but is proteolytically processed at furin consensus sequence to produce soluble protein. Processed, soluble BAFF adopts a usual trimeric form that appears to be the primary bioactive form of BAFF, but it is the only member of the family that can also further assemble as an ordered, capsid-like structure comprising twenty trimers. A trimeric BAFF ligand binds to three independent BAFFR (TNFRSF13C) receptor to initiate signalling (Liu et al. 2002, 2003, Mackay & Schneider 2009). BAFFR is predominantly expressed in B cells and contains a typical TNF receptor-associated factor (TRAF)-binding sites in their cytoplasmic domains which interacts with TRAF3 but not TRAF2 upon ligand interaction (Morrison et al. 2005). BAFF can also bind to other TNF superfamily (TNFSF) members, B cell maturation antigen (BCMA also known as TNFRSF17) and transmembrane activator and CAML interactor (TAC also known as TNFRSF13B) (Gross et al. 2000).
RANK:RANKL,sRANKL trimerArrowR-HSA-5676589 (Reactome)
RANK:RANKL,sRANKL trimerR-HSA-5676592 (Reactome)
RANKL,sRANKL trimerR-HSA-5676589 (Reactome)
TNF(1-233) trimerR-HSA-5668404 (Reactome)
TNFA trimer:TNFR2 trimerArrowR-HSA-5668467 (Reactome)
TNFA trimer:TNFR2 trimerR-HSA-5668417 (Reactome)
TNFA trimer:TNFR2ArrowR-HSA-5668404 (Reactome)
TNFA trimer:TNFR2R-HSA-5668467 (Reactome)
TNFA:TNFR2 heterotrimer:cIAP1,2:TRAF2:TRAF3:NIKArrowR-HSA-5668417 (Reactome)
TNFA:TNFR2,BAFF:BAFFR,TWEAK:Fn14,Lymphotoxin:LTBR,RANKL:RANK,CD40L:CD40ArrowR-HSA-5668481 (Reactome)
TNFRSF11AR-HSA-5676589 (Reactome)
TNFRSF11AR-HSA-5676592 (Reactome)
TNFRSF12AR-HSA-5669023 (Reactome)
TNFRSF13CR-HSA-5676599 (Reactome)
TNFRSF1BR-HSA-5668404 (Reactome)
TNFRSF1BR-HSA-5668467 (Reactome)
TNFSF:TNFRSF heterotrimer:K63polyUb-cIAP1,2:TRAF2:TRAF3:NIKArrowR-HSA-5668414 (Reactome)
TNFSF:TNFRSF heterotrimer:K63polyUb-cIAP1,2:TRAF2:TRAF3:NIKR-HSA-5668454 (Reactome)
TNFSF:TNFRSF heterotrimer:K63polyUb-cIAP1,2:TRAF2:TRAF3:NIKTBarR-HSA-5668534 (Reactome)
TNFSF:TNFRSF heterotrimer:K63polyUb-cIAP1,2:TRAF2:TRAF3:NIKmim-catalysisR-HSA-5668454 (Reactome)
TNFSF:TNFRSF heterotrimer:TRAF2:K63polyUb-cIAP1,2:K48polyUb-TRAF3:NIKArrowR-HSA-5668454 (Reactome)
TNFSF:TNFRSF heterotrimer:TRAF2:K63polyUb-cIAP1,2:K48polyUb-TRAF3:NIKR-HSA-5668481 (Reactome)
TRAF1:TRAF2:K63polyUb-cIAP1,2ArrowR-HSA-5668481 (Reactome)
TRAF2:cIAP1,2ArrowR-HSA-5668534 (Reactome)
TRAF2:cIAP1,2R-HSA-5668543 (Reactome)
TRAF3:NIKR-HSA-5668543 (Reactome)
TRAF3ArrowR-HSA-5668534 (Reactome)
cIAP1,2:TRAF2:TRAF3:NIKArrowR-HSA-5668543 (Reactome)
cIAP1,2:TRAF2:TRAF3:NIKR-HSA-5668417 (Reactome)
cIAP1,2:TRAF2:TRAF3:NIKR-HSA-5668534 (Reactome)
cIAP1,2:TRAF2:TRAF3:NIKR-HSA-5676593 (Reactome)
cIAP1,2:TRAF2:TRAF3:NIKR-HSA-5676595 (Reactome)
cIAP1,2:TRAF2:TRAF3:NIKR-HSA-5676596 (Reactome)
cIAP1,2:TRAF2:TRAF3:NIKR-HSA-5676597 (Reactome)
cIAP1,2:TRAF2:TRAF3:NIKR-HSA-5676598 (Reactome)
cIAP1,2:TRAF2:TRAF3:NIKmim-catalysisR-HSA-5668534 (Reactome)
lymphotoxin,TNFSF14 trimerR-HSA-5668789 (Reactome)
sBAFF trimerR-HSA-5676599 (Reactome)
sTWEAK,TWEAK homotrimersR-HSA-5669023 (Reactome)
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