BioPAX pathway converted from "Toll Like Receptor 3 (TLR3) Cascade" in the Reactome database.

Toll Like Receptor 3 (TLR3) Cascade

Toll-like receptor 3 (TLR3) as was shown for mammals is expressed on myeloid dendritic cells, respiratory epithelium, macrophages, and appears to play a central role in mediating the antiviral and inflammatory responses of the innate immunity in combating viral infections.Mammalian TLR3 recognizes dsRNA, and that triggers the receptor to induce the activation of NF-kappaB and the production of type I interferons (IFNs). dsRNA-stimulated phosphorylation of two specific TLR3 tyrosine residues (Tyr759 and Tyr858) is essential for initiating TLR3 signaling pathways.

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gay, NJ, 2006-04-24 16:48:17Edited: Shamovsky, V, 2011-08-12

Viral dsRNA binds the Toll-Like Receptor 3 (TLR3)

Viral dsRNA triggers an antiviral pathway mediated by toll like receptor 3. TLR3 dimerization occurs upon ligand binding to positivly charged residues on the ectodomain termini of TLR3 wich are responsible for the interaction with sugar-phosphate groups of dsRNA.

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gay, NJ, 2006-04-24 16:48:17Edited: Shamovsky, V, 2012-02-19

Converted from EntitySet in Reactome

Reactome DB_ID: 9038432

endosome lumenGO0031904

TLR3 ligand [endosome lumen]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactomehttp://www.reactome.org

Reactome DB_ID: 2000341

endosome membraneGO0010008

UniProt:O15455 TLR3

TLR3

TLR3FUNCTION Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion and the inflammatory response.SUBUNIT Monomer and homodimer; dimerization is triggered by ligand-binding, the signaling unit is composed of one ds-RNA of around 40 bp and two TLR3 molecules, and lateral clustering of signaling units along the length of the ds-RNA ligand is required for TLR3 signal transduction. Interacts (via transmembrane domain) with UNC93B1; the interaction is required for transport from the ER to the endosomes. Interacts with SRC; upon binding of double-stranded RNA. Interacts with TICAM1 (via the TIR domain) in response to poly(I:C) and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). The tyrosine-phosphorylated form (via TIR domain) interacts with WDFY1 (via WD repeat 2) in response to poly(I:C) (PubMed:25736436).TISSUE SPECIFICITY Expressed at high level in placenta and pancreas. Also detected in CD11c+ immature dendritic cells. Only expressed in dendritic cells and not in other leukocytes, including monocyte precursors. TLR3 is the TLR that is expressed most strongly in the brain, especially in astrocytes, glia, and neurons.DOMAIN ds-RNA binding is mediated by LRR 1 to 3, and LRR 17 to 18.PTM Heavily N-glycosylated, except on that part of the surface of the ectodomain that is involved in ligand binding.PTM TLR3 signaling requires a proteolytic cleavage mediated by cathepsins CTSB and CTSH, the cleavage occurs between amino acids 252 and 346. The cleaved form of TLR3 is the predominant form found in endosomes.POLYMORPHISM The Phe-412 allele (dbSNP:rs3775291) occurs with a frequency of 30% in populations with European and Asian ancestry, and confers some natural resistance to HIV-1 infection.SIMILARITY Belongs to the Toll-like receptor family.

Homo sapiens

NCBI Taxonomy9606UniProtO15455

Chain Coordinates

EQUAL

904

EQUAL

Reactome DB_ID: 167985

viral dsRNA :TLR3 [endosome membrane]

viral dsRNA :TLR3

Converted from EntitySet in Reactome

Reactome DB_ID: 9038432

Reactome DB_ID: 2000341

EQUAL

904

EQUAL

Reactome Database ID Release 70167985Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167985ReactomeR-HSA-167985

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-167985.4Reactome Database ID Release 70168092Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168092ReactomeR-HSA-168092

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168092.411607032Pubmed2001Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3Alexopoulou, LHolt, ACMedzhitov, RFlavell, RANature 413:732-818420935Pubmed2008Structural basis of toll-like receptor 3 signaling with double-stranded RNALiu, LBotos, IWang, YLeonard, JNShiloach, JSegal, DMDavies, DRScience 320:379-81

Viral dsRNA:TLR3 recruits TRIF (TICAM1)

TIR-domain-containing adaptor inducing interferon-beta (TRIF or TICAM1) was shown to play an essential role in TLR3 signaling. All poly(I:C)-induced pathways leading to NFkB and IRF3 activation were abolished in TRIF-/- mice [Yamamoto et al. 2003].

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gay, NJ, 2006-04-24 16:48:17Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 166170

cytosolGO0005829

UniProt:Q8IUC6 TICAM1

TICAM1

PRVTIRBTICAM1TRIFFUNCTION Involved in innate immunity against invading pathogens. Adapter used by TLR3, TLR4 (through TICAM2) and TLR5 to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis (PubMed:12471095, PubMed:12539043, PubMed:14739303). Ligand binding to these receptors results in TRIF recruitment through its TIR domain (PubMed:12471095, PubMed:12539043, PubMed:14739303). Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively (PubMed:12471095, PubMed:12539043, PubMed:14739303). Phosphorylation by TBK1 on the pLxIS motif leads to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent immunity against invading pathogens (PubMed:25636800). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of proinflammatory cytokines (By similarity).SUBUNIT Homodimer (PubMed:12539043). Found in a multi-helicase-TICAM1 complex at least composed of DHX36, DDX1, DDX21 and TICAM1; this complex exists in resting cells with or without poly(I:C) RNA ligand stimulation. Interacts (via TIR domain) with DDX21 (via C-terminus). Interacts (via TIR domain) with DHX36 (via C-terminus) (By similarity). Interacts with AZI2 and IRF7 (PubMed:12471095, PubMed:15611223). Interacts with TICAM2 in TLR4 recruitment (PubMed:12721283, PubMed:25736436). Interaction with PIAS4 inhibits the TICAM1-induced NF-kappa-B, IRF and IFNB1 activation (PubMed:15251447). Interacts with IKBKB and IKBKE. Interaction with SARM1 blocks TICAM1-dependent transcription factor activation (PubMed:16964262). Interacts with TRAF3 (By similarity). Interacts (when phosphorylated) with IRF3; following activation and phosphorylation on the pLxIS motif by TBK1, recruits IRF3 (PubMed:12471095, PubMed:14739303, PubMed:25636800, PubMed:27302953). Interacts with TBK1, TRAF6 and RIPK1 and these interactions are enhanced in the presence of WDFY1 (PubMed:14982987, PubMed:25736436). Interacts with TRAFD1 (By similarity). Interacts with UBQLN1 (via UBA domain) (PubMed:21695056). Interacts with TLR4 in response to LPS in a WDFY1-dependent manner (By similarity). Interacts with WDFY1 in response to poly(I:C) (By similarity). Interacts (via the TIR domain) with TLR3 in response to poly(I:C) and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TRIM56 (PubMed:22948160). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of proinflammatory cytokines (By similarity). Interacts (via the TIR domain) with TLR5 (PubMed:20855887).SUBUNIT (Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction allows the cleavage of TICAM1/TRIF and subsequent suppression of host innate immunity.TISSUE SPECIFICITY Ubiquitously expressed but with higher levels in liver.DOMAIN The pLxIS motif constitutes an IRF3-binding motif: following phosphorylation by TBK1, the phosphorylated pLxIS motif of TICAM1 recruits IRF3 (PubMed:25636800). IRF3 is then phosphorylated and activated by TBK1 to induce type-I interferons and other cytokines (PubMed:25636800).DOMAIN The N-terminal region is essential for activation of the IFNB promoter activity.DOMAIN The N-terminal domain (TRIF-NTD) is globular and consists of two alpha-helical subdomains connected by a 14-residue linker. It shares structural similarity with IFIT family members N-terminal regions.PTM Phosphorylated by TBK1 (PubMed:14530355, PubMed:25636800). Following activation, phosphorylated by TBK1 at Ser-210 in the pLxIS motif (PubMed:25636800). The phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading to recruitment of the transcription factor IRF3 to induce type-I interferons and other cytokines (PubMed:25636800, PubMed:27302953).PTM Polyubiquitinated by TRIM38 with 'Lys-48'-linked chains, leading to proteasomal degradation.PTM (Microbial infection) Cleaved and degraded by hepatitis A virus (HAV) protein 3CD allowing the virus to disrupt host TLR3 signaling.PTM (Microbial infection) Cleaved by Seneca Valley virus protease 3C allowing the virus to disrupt host TLR3 signaling.

UniProtQ8IUC6

EQUAL

712

EQUAL

Reactome DB_ID: 167985

Reactome DB_ID: 168907

viral dsRNA:TLR3:TICAM1 [endosome membrane]

viral dsRNA:TLR3:TICAM1

viral dsRNA:TLR3:TRIF

Reactome DB_ID: 167985

Reactome DB_ID: 450316

EQUAL

712

EQUAL

Reactome Database ID Release 70168907Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168907ReactomeR-HSA-168907

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168907.3Reactome Database ID Release 70168929Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168929ReactomeR-HSA-168929

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168929.312855817Pubmed2003Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathwayYamamoto, MSato, SHemmi, HHoshino, KKaisho, TSanjo, HTakeuchi, OSugiyama, MOkabe, MTakeda, KScience 301:640-312539043Pubmed2003TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta inductionOshiumi, HMatsumoto, MFunami, KAkazawa, TSeya, TNat Immunol 4:161-714517278Pubmed2003LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adaptersFitzgerald, Katherine ARowe, DCBarnes, BJCaffrey, DRVisintin, ALatz, EMonks, BGPitha-Rowe, Paula MGolenbock, DTJ Exp Med 198:1043-55

SARM binds viral dsRNA:TLR3:TICAM1

Negative regulator SARM binds to TRIF within activated TLR3 complexSARM (sterile alpha-and armadillo-motif-containing protein) is a TIR-domain-containing adaptor, which functions as a negative regulator of TRIF (TICAM1)-dependent Toll-like receptor signaling in humans. A pairwise yeast two-hybrid assay demonstrated that SARM is capable of binding directly to TICAM1 (Carty M et al. 2006). GST pulldown studies suggest that protein-protein interactions occur between the TIR domains of SARM and TICAM1 (Carlsson E et al. 2016). The complex of TICAM1:SARM is thought to inhibit downstream TRIF signaling by preventing the recruitment of TRIF effector proteins (Carty M et al. 2006).SARM expression was shown to inhibit poly(I:C)-induced TICAM1-dependent NFkappaB activaion, RANTES production and IRF activation in human embryonic kidney HEK293 cells (Carty M et al. 2006). Moreover, suppression of endogenous SARM expression by siRNA led to enhanced TLR3- and TLR4-dependent gene induction in both transformed HEK293 and primary PBMC cells (Carty M et al. 2006), Thus, SARM associates with TICAM1 via its TIR and sterile-alpha motif (SAM) domains to block the induction of proinflammatory genes downstream TLR3.

Authored: Shamovsky, V, 2012-05-15Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2012-11-19

Reactome DB_ID: 2559572

UniProt:Q6SZW1-1 SARM1

SARM1

KIAA0524SARM1SAMD2SARMFUNCTION Negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway which plays a pivotal role in activating axonal degeneration following injury. Promotes Wallerian degeneration an injury-induced axonal death pathway which involves degeneration of an axon distal to the injury site. Can activate neuronal death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. Involved in innate immune response. Inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38.SUBUNIT Interacts with TICAM1/TRIF and thereby interferes with TICAM1/TRIF function. Interacts with MAPK10/JNK3 and SDC2 (via cytoplasmic domain) (By similarity).TISSUE SPECIFICITY Predominantly expressed in brain, kidney and liver. Expressed at lower level in placenta.INDUCTION Up-regulated by lipopolysaccharides (LPS).CAUTION Was initially (PubMed:11386760) reported to contain ARM repeats. Such repeats are however not predicted by any detection method.

UniProtQ6SZW1-1

EQUAL

724

EQUAL

Reactome DB_ID: 168907

Reactome DB_ID: 9014322

SARM:TICAM1:viral dsRNA:TLR3 [endosome membrane]

SARM:TICAM1:viral dsRNA:TLR3

SARM:TICAM1:activated TLR3SARM:TRIF:viral dsRNA:TLR3

Reactome DB_ID: 2559572

EQUAL

724

EQUAL

Reactome DB_ID: 168907

Reactome Database ID Release 709014322Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014322ReactomeR-HSA-9014322

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014322.2Reactome Database ID Release 709014320Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014320ReactomeR-HSA-9014320

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014320.226592460Pubmed2016SARM modulates MyD88-mediated TLR activation through BB-loop dependent TIR-TIR interactionsCarlsson, EmilDing, Jeak LingByrne, BernadetteBiochim. Biophys. Acta 1863:244-5316964262Pubmed2006The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signalingCarty, MichaelGoodbody, RorySchröder, MartinaStack, JulianneMoynagh, Paul NBowie, Andrew GNat. Immunol. 7:1074-81GO0034128

GO biological process

TICAM1-dependent activation of IRF3/IRF7

TLR3-mediated TICAM1-dependent activation of IRF3/IRF7TLR3-mediated TRIF-dependent activation of IRF3/IRF7Activation of IRF3/IRF7 mediated by TBK1/IKK epsilonCell stimulation with viral ds RNA leads to the activation of two IKK-related serine/threonine kinases, TBK1 and IKK-i which directly phosphorylate IRF3 and IRF7 promoting their dimerization and translocation into the nucleus. Although both kinases show structural and functional similarities, it seems that TBK1 and IKK-i differ in their regulation of downstream signaling events of TLR3.IRF3 activation and IFN-b production by poly(I:C) are decreased in TBK1-deficient mouse fibroblasts, whereas normal activation was observed in the IKK-i-deficient fibroblasts. However, in double-deficient mouse fibroblasts, the activation of IRF3 is completely abolished, suggesting a partially redundant functions of TBK1 and IKK-i (Hemmi et al. 2004).TLR3 recruits and activates PI3 kinase (PI3K), which activates the downstream kinase, Akt, leading to full phosphorylation and activation of IRF-3 [Sarkar SN et al 2004]. When PI3K is not recruited to TLR3 or its activity is blocked, IRF-3 is only partially phosphorylated and fails to bind the promoter of the target gene.

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-11-30Reviewed: Fitzgerald, Katherine A, 2012-11-13Reviewed: Masci, Anna Maria, 2014-05-16Edited: Shamovsky, V, 2010-11-16

TRAF3 binds to TRIF:activated TLR3 complex

Tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) is a ubiquitin ligase recruited to both MYD88- and TRIF-assembled signalling complexes [Hacker H et al 2006]. However, TRAF3 controls the production of interferon and proinflammatory cytokines in different ways [Tseng PH et al 2010]. Positive or negative type of regulation is dictated by TRAF3 subcellular distribution and its mode of ubiquitination. Thus, TRIF-mediated signaling initiated on endosomes triggers TRAF3 self-ubiquitination through noncanonical (K63-linked) polyubiquitination, which is essential for activation of IRF3/7 and the interferon response. In contrast, during MyD88-dependent signaling initiated from plasma membrane TRAF3 functions as a negative regulator of inflammatory cytokines and mitogen-activated protein kinases (MAPKs), unless it undergoes degradative (K48-linked) polyubiquitination mediated by TRAF6 and a pair of the ubiquitin ligases cIAP1 and cIAP2. The degradation of TRAF3 is essential for MAPK activation via TAK1 and MEKK1 [Tseng PH et al 2010].

Authored: Shamovsky, V, 2012-04-26Reviewed: D'Eustachio, P, 2012-05-25Reviewed: Fitzgerald, Katherine A, 2012-11-13Reviewed: Masci, Anna Maria, 2014-05-16Edited: Shamovsky, V, 2012-05-25

Reactome DB_ID: 914241

UniProt:Q13114 TRAF3

TRAF3

CAP1TRAF3CRAF1FUNCTION Regulates pathways leading to the activation of NF-kappa-B and MAP kinases, and plays a central role in the regulation of B-cell survival. Part of signaling pathways leading to the production of cytokines and interferon. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Plays a role in the regulation of antiviral responses. Is an essential constituent of several E3 ubiquitin-protein ligase complexes. May have E3 ubiquitin-protein ligase activity and promote 'Lys-63'-linked ubiquitination of target proteins. Inhibits activation of NF-kappa-B in response to LTBR stimulation. Inhibits TRAF2-mediated activation of NF-kappa-B. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14.SUBUNIT Homotrimer. Heterotrimer with TRAF2 and TRAF5. Interacts with LTBR/TNFRSF3, TNFRSF4, TNFRSF5/CD40, TNFRSF8/CD30, TNFRSF13C TNFRSF17/BCMA, TLR4 and EDAR. Interacts with MAP3K5, MAP3K14, TRAIP/TRIP, TDP2/TTRAP, TANK/ITRAF and TRAF3IP1. Interaction with TNFRSF5/CD40 is modulated by TANK/ITRAF, which competes for the same binding site. Interacts with TICAM1. Interacts with TRAFD1. Interacts with OTUB1, OTUB2 and OTUD5. Interacts with RNF216, MAVS, OPTN and TBK1. Identified in a complex with TRAF2, MAP3K14 and BIRC3. Interacts with BIRC2 and BIRC3. Upon exposure to bacterial lipopolysaccharide (LPS), recruited to a transient complex containing TLR4, TRAF3, TRAF6, IKBKG, MAP3K7, MYD88, TICAM1, BIRC2, BIRC3 and UBE2N (By similarity). Interacts with Epstein-Barr virus protein LMP1. Interacts (via RING-type zinc finger domain) with SRC. Interacts with CARD14. Interacts (via MATH domain) with PTPN22; the interaction promotes TRAF3 polyubiquitination (PubMed:23871208).DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.DOMAIN The Ring-type zinc finger domain is required for its function in down-regulation of NFKB2 proteolytic processing.PTM Undergoes 'Lys-48'-linked polyubiquitination, leading to its proteasomal degradation in response to signaling by TNFSF13B, TLR4 or through CD40. 'Lys-48'-linked polyubiquitinated form is deubiquitinated by OTUD7B, preventing TRAF3 proteolysis and over-activation of non-canonical NF-kappa-B. Undergoes 'Lys-63'-linked ubiquitination during early stages of virus infection, and 'Lys-48'-linked ubiquitination during later stages. Undergoes both 'Lys-48'-linked and 'Lys-63'-linked ubiquitination in response to TLR3 and TLR4 signaling. Deubiquitinated by OTUB1, OTUB2 and OTUD5.SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily.

UniProtQ13114

EQUAL

568

EQUAL

Reactome DB_ID: 168907

Reactome DB_ID: 9013984

TRAF3:TICAM1:viral dsRNA:TLR3 [endosome membrane]

TRAF3:TICAM1:viral dsRNA:TLR3

TRAF3:TRIF:activated TLR3

Reactome DB_ID: 914241

EQUAL

568

EQUAL

Reactome DB_ID: 168907

Reactome Database ID Release 709013984Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013984ReactomeR-HSA-9013984

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013984.2Reactome Database ID Release 709013992Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013992ReactomeR-HSA-9013992

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013992.216306936Pubmed2006Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral responseOganesyan, GSaha, SKGuo, BHe, JQShahangian, AZarnegar, BPerry, ACheng, GNature 439:208-1116306937Pubmed2006Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6Häcker, HRedecke, VBlagoev, BKratchmarova, IHsu, LCWang, GGKamps, MPRaz, EWagner, HHäcker, GMann, MKarin, MNature 439:204-719898473Pubmed2010Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokinesTseng, PHMatsuzawa, AZhang, WMino, TVignali, DAKarin, MNat Immunol 11:70-5

6.3.2.19

Auto-ubiquitination of TRAF3 within activated TLR3 complex

TRIF(TICAM1) signaling activates TRAF3 self-mediated polyubiquitination trough Lys-63 of ubiquitin. The ubiquitinated TRAF3 in turn activates the interferon response (Tseng PH et al. 2010).

Authored: Shamovsky, V, 2012-04-26Reviewed: D'Eustachio, P, 2012-05-25Reviewed: Fitzgerald, Katherine A, 2012-11-13Reviewed: Masci, Anna Maria, 2014-05-16Edited: Shamovsky, V, 2012-05-25

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBB(1-76) [cytosol]UBC(457-532) [cytosol]UBC(533-608) [cytosol]UBB(77-152) [cytosol]RPS27A(1-76) [cytosol]UBC(1-76) [cytosol]UBA52(1-76) [cytosol]UBB(153-228) [cytosol]UBC(153-228) [cytosol]UBC(305-380) [cytosol]UBC(609-684) [cytosol]UBC(381-456) [cytosol]UBC(229-304) [cytosol]UBC(77-152) [cytosol]

UniProtP0CG47UniProtP0CG48UniProtP62979UniProtP62987

Reactome DB_ID: 9013984

Reactome DB_ID: 9013989

K63polyUb-TRAF3:TICAM1:activated TLR3 [endosome membrane]

K63polyUb-TRAF3:TICAM1:activated TLR3

K63polyUb-TRAF3:TRIF:activated TLR3

Reactome DB_ID: 936402

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at unknown position

ubiquitinylated lysine [MOD:01148]

EQUAL

568

EQUAL

Reactome DB_ID: 168907

Reactome Database ID Release 709013989Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013989ReactomeR-HSA-9013989

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013989.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9013984

GO0004842

GO molecular function

Reactome Database ID Release 709014563Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014563Reactome Database ID Release 709013974Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013974ReactomeR-HSA-9013974

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013974.2

TANK binds K63-poly-Ub-TRAF3:TICAM1:activated TLR3

TRAF family member-associated NFkB activator (TANK or ITRAF) is a TRAF-binding protein that has been implicated in RLR, TNFR and IL-1R/TLR signaling pathways in mammals (Rothe M et a.l 1996; Pomerantz JL and Baltimore D 1999; Li C et al. 2002; Guo B and Cheng G 2007; Konno H 2009). TANK was shown to interact with TBK1, IKK epsilon, IPS-1, TRIF (TICAM1), IRF3 and is thought to be a part of the TRAF3-containing complex (Pomerantz JL and Baltimore D 1999; Guo B and Cheng G 2007; Gatot JC et al. 2007). Upon microbe stimulation TANK is believed to induce IRF-dependent type I IFN production in mammalian cells by linking kinase TBK1 or IKK epsilon with upstream mediators TRAF3/6 (Guo B and Cheng G 2007; Gatot JC et al. 2007). In addition, TANK is thought to act synergistically with IKK epsilon or TBK1 to link them to IKK complex via interaction with NEMO (IKK gamma), where TBK1/IKK epsilon may modulate NFkB activation (Chariot A et al. 2002). TANK influence on NFkB activation was found to occur via either positive or negative regulation (Guo B and Cheng G 2007, Konno H et al. 2009; Pomerantz JL and Baltimore D 1999; Kawagoe T et al. 2009). Two other adaptor proteins NAK-associated protein 1 (NAP1) and SINTBAD (not shown here) have been implicated in TBK1/IKKepsilon-mediated activation of IRF3 (Sasai M et al. 2005; Ryzhakov G and Randow F 2007). Structural and functional studies showed that TANK, NAP1 and SINTBAD share a common region which mediates association with the coiled-coil 2 in TBK1 (Ryzhakov G and Randow F 2007; Goncalves A et al. 2011; Larabi A et al. 2013; Tu D et al. 2013). TANK, NAP1 and SINTBAD were found to compete for TBK1 binding (Ryzhakov G and Randow F 2007; Goncalves A et al. 2011), TBK1 is thought to form alternative complexes with each adaptor TANK, NAP1 or SINTBAD, rather than a single large multiprotein complex containing all three adaptors (Goncalves A et al. 2011; Larabi A et al. 2013).

Authored: Shamovsky, V, 2014-05-16Reviewed: Masci, Anna Maria, 2014-05-16Edited: Shamovsky, V, 2014-05-16

Reactome DB_ID: 9013989

Reactome DB_ID: 933407

UniProt:Q92844 TANK

TANK

ITRAFTRAF2TANKFUNCTION Adapter protein involved in I-kappa-B-kinase (IKK) regulation which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity. Acts as a regulator of TRAF function by maintaining them in a latent state. Blocks TRAF2 binding to LMP1 and inhibits LMP1-mediated NF-kappa-B activation. Negatively regulates NF-kappaB signaling and cell survival upon DNA damage (PubMed:25861989). Plays a role as an adapter to assemble ZC3H12A, USP10 in a deubiquitination complex which plays a negative feedback response to attenuate NF-kappaB activation through the deubiquitination of IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage (PubMed:25861989). Promotes UBP10-induced deubiquitination of TRAF6 in response to DNA damage (PubMed:25861989). May control negatively TRAF2-mediated NF-kappa-B activation signaled by CD40, TNFR1 and TNFR2.SUBUNIT Homodimer. Found in a deubiquitination complex with TANK, USP10 and ZC3H12A; this complex inhibits genotoxic stress- or interleukin-1-beta-mediated NF-kappaB activation by promoting IKBKG or TRAF6 deubiquitination (PubMed:25861989). Interacts with IKBKG; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with TRAF6; this interaction increases in response to DNA damage and recruits USP10 to the ubiquitinated TRAF6 (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with TBK1 (PubMed:10581243, PubMed:21931631). Interacts with IKBKE (PubMed:17568778). Interacts also with TRAF1, TRAF2, and TRAF3 by binding to their TRAF-C domains; the interaction with TRAF2 is disrupted by the phosphorylation of TANK by IKBKE (PubMed:10759890, PubMed:12005438). Interacts more strongly with TRAF1 and TRAF2 than TRAF3 (PubMed:10759890, PubMed:12005438). Interacts with IKBKG; the interaction is enhanced by IKBKE and TBK1 (PubMed:12133833). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein C6 (PubMed:21931555).SUBUNIT (Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction allows the cleavage of TANK and subsequent suppression of host innate immunity.TISSUE SPECIFICITY Ubiquitous.PTM Phosphorylated by IKBKE.PTM (Microbial infection) Cleaved by encephalomyocarditis virus (EMCV) protease 3C (PubMed:26363073). This cleavage allows the virus to disrupt the TANK-TBK1-IKKepsilon-IRF3 complex, thereby inhibiting the induction of the IFN-beta signal pathway (PubMed:28487378).PTM (Microbial infection) Cleaved by Seneca Valley virus protease 3C allowing the virus to suppress interferon type-I through both RIG-I and Toll-like receptor-dependent pathways.

UniProtQ92844

EQUAL

425

EQUAL

Reactome DB_ID: 9013980

TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3 [endosome membrane]

TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3

TANK:K63-poly-Ub-TRAF3:TRIF:activated TLR3TANK:K63-poly-Ub-TRAF3:TICAM1:activated TLR3

Reactome DB_ID: 9013989

Reactome DB_ID: 933407

EQUAL

425

EQUAL

Reactome Database ID Release 709013980Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013980ReactomeR-HSA-9013980

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013980.2Reactome Database ID Release 709013985Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013985ReactomeR-HSA-9013985

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013985.210581243Pubmed1999NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinasePomerantz, JLBaltimore, DEMBO J 18:6694-70417327220Pubmed2007Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANKGuo, BCheng, GJ Biol Chem 282:11817-2619479062Pubmed2009TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNAKonno, HYamamoto, TYamazaki, KGohda, JAkiyama, TSemba, KGoto, HKato, AYujiri, TImai, TKawaguchi, YSu, BTakeuchi, OAkira, ShizuoTsunetsugu-Yokota, YInoue, JPLoS One 4:e567417047224Pubmed2006Regulation and function of IKK and IKK-related kinasesHacker, HKarin, MSci STKE 2006:re138710854Pubmed1996I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transductionRothe, MXiong, JShu, H BWilliamson, KGoddard, AGoeddel, DVProc. Natl. Acad. Sci. U.S.A. 93:8241-617568778Pubmed2007SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANKRyzhakov, GrigoryRandow, FelixEMBO J. 26:3180-9021931631Pubmed2011Functional dissection of the TBK1 molecular networkGoncalves, AdrianaBürckstümmer, TilmannDixit, EvelynScheicher, RuthGórna, Maria WKarayel, EvrenSugar, CristinaStukalov, AlexeyBerg, TiinaKralovics, RobertPlanyavsky, MelanieBennett, Keiryn LColinge, JacquesSuperti-Furga, GiulioPLoS ONE 6:e2397119668221Pubmed2009TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritisKawagoe, TTakeuchi, OTakabatake, YKato, HIsaka, YTsujimura, TAkira, ShizuoNat Immunol 10:965-7212005438Pubmed2002Downstream regulator TANK binds to the CD40 recognition site on TRAF3Li, ChenglongNi, Chao-ZhouHavert, Marnie LCabezas, EdelmiraHe, JeannieKaiser, DonaldReed, John CSatterthwait, Arnold CCheng, GenhongEly, Kathryn RStructure 10:403-1123453971Pubmed2013Crystal structure and mechanism of activation of TANK-binding kinase 1Larabi, AmedeDevos, Juliette MNg, Sze-LingNanao, Max HRound, AdamManiatis, TomPanne, DanielCell Rep 3:734-4615611223Pubmed2005Cutting Edge: NF-kappaB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activationSasai, MiwaOshiumi, HMatsumoto, MInoue, NFujita, FumitakaNakanishi, MakotoSeya, TJ. Immunol. 174:27-3012133833Pubmed2002Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinasesChariot, ALeonardi, AMuller, JBonif, MBrown, KSiebenlist, UJ Biol Chem 277:37029-3617823124Pubmed2007Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAFGatot, Jean-StéphaneGioia, RomainChau, Tieu-LanPatrascu, FéliciaWarnier, MichaelClose, PierreChapelle, Jean-PaulMuraille, EricBrown, KeithSiebenlist, UlrichPiette, JacquesDejardin, EmmanuelChariot, AlainJ. Biol. Chem. 282:31131-4623453972Pubmed2013Structure and ubiquitination-dependent activation of TANK-binding kinase 1Tu, DaqiZhu, ZehuaZhou, Alicia YYun, Cai-hongLee, Kyung-EunToms, Angela VLi, YDunn, Gavin PChan, EdmondThai, TranYang, ShenghongFicarro, Scott BMarto, Jarrod AJeon, HHahn, WCBarbie, David AEck, Michael JCell Rep 3:747-58

TANK is ubiquitinated within TANK:K63polyUb-TRAF3:TICAM1:TLR3:viral dsRNA

TANK is ubiquitinated within TANK:K63polyUb-TRAF3:TICAM1:activated TLR3Upon stimulation by pathogen-associated inflammatory signals TANK associates with TRAF3 which may result in K63-linked ubiquitination of TANK (Gatot JC et al. 2007). How the ubiquitination of TANK contributes to the activation of TBK1 and/or IKKepsilon remains unclear.

Authored: Shamovsky, V, 2014-05-16Reviewed: Masci, Anna Maria, 2014-05-16Edited: Shamovsky, V, 2014-05-16

Reactome DB_ID: 9013980

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 9013976

K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNA [endosome membrane]

K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNA

K63pUb-TANK:K63pUb-TRAF3:TRIF:activated TLR3

Reactome DB_ID: 5362480

ubiquitinylated lysine (K63polyUb [cytosol]) at unknown position

EQUAL

425

EQUAL

Reactome DB_ID: 9013989

Reactome Database ID Release 709013976Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013976ReactomeR-HSA-9013976

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013976.2Reactome Database ID Release 709013990Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013990ReactomeR-HSA-9013990

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013990.2

Recruitment of TBK1/IKK epsilon to K63-pUb-TANK:K63-pUb-TRAF3:TRIF:activated TLR3 followed by their phosphorylation

Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) and inhibitor of kappaB kinase epsilon (IKKi) induce type I interferon expression and modulate nuclear factor kappa B (NFkB) signaling (Fitzgerald KA et al. 2003; Hemmi H et al. 2004). The structural studies of TBK1 revealed a dimeric assembly which is mediated by several interfaces involving kinase domain (KD), a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD) of TBK1 (Larabi A et al. 2013; Tu D et al. 2013). ULD of TBK1 and IKKi was involved in the control of kinase activation, substrate presentation and downstream signaling (Ikeda F et al 2007; Tu D et al. 2013). An intact TBK1 dimer was a subject to K63-linked polyubiquitination on lysines 30 and 401 (Tu D et al. 2013). Activation of TBK1 rearranged the KD into an active conformation while maintaining the overall dimer conformation (Larabi A et al. 2013). The ubiquitination sites and dimer contacts are conserved in the close homolog IKKi (Tu D et al. 2013). The activation of TBK1 and IKKi may occur through autophosphorylation or via activity of a distinct protein kinase (Clark et al. 2009). Other studies demonstrated an essential role of TRAF3 in the activation of TBK1 (Hacker et al 2006). TBK1 and IKKi were found to interact with scaffold proteins TANK (TRAF family member associated NFkB activator), NAP1 (NAK-associated protein 1), SINTBAD (similar to NAP1 TBK1 adaptor) which connect TBK1/IKKi to pathogen-activated signaling cascades (Pomerantz JL and Baltimore D 1999; Guo B and Cheng G 2007; Gatot JC et al. 2007; Ryzhakov G and Randow F 2007; Goncalves A et al. 2011).

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-11-30Reviewed: Fitzgerald, Katherine A, 2012-11-13Reviewed: Masci, Anna Maria, 2014-05-16Edited: Shamovsky, V, 2014-05-16

Reactome DB_ID: 113592

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616Converted from EntitySet in Reactome

Reactome DB_ID: 450329

IKK related kinases TBK1/IKK epsilon [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityIKBKE [cytosol]TBK1 [cytosol]

UniProtQ14164UniProtQ9UHD2

Reactome DB_ID: 9013976

Reactome DB_ID: 9013982

activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKi [endosome membrane]

activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKi

Reactome DB_ID: 9013976

Converted from EntitySet in Reactome

Reactome DB_ID: 450251

activated TBK1/IKK epsilon [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S172-IKBKE [endosome membrane]p-S172-TBK1 [endosome membrane]

Reactome Database ID Release 709013982Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013982ReactomeR-HSA-9013982

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013982.2

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADP

ChEBI456216Reactome Database ID Release 709013986Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013986ReactomeR-HSA-9013986

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013986.212692549Pubmed2003IKKepsilon and TBK1 are essential components of the IRF3 signaling pathwayFitzgerald, Katherine AMcWhirter, SMFaia, KLRowe, DCLatz, EGolenbock, DTCoyle, AJLiao, SMManiatis, TNat Immunol 4:491-617599067Pubmed2007Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genesIkeda, FHecker, CMRozenknop, ANordmeier, RDRogov, VHofmann, KAkira, ShizuoDötsch, VDikic, IEMBO J 26:3451-6219307177Pubmed2009Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activationClark, KPlater, LPeggie, MCohen, PJ Biol Chem 284:14136-4615210742Pubmed2004The roles of two IkappaB kinase-related kinases in lipopolysaccharide andHemmi, HTakeuchi, OSato, SYamamoto, MKaisho, TSanjo, HKawai, THoshino, KTakeda, KJ Exp Med 199:1641-50

IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR3

Two members of the interferon regulatory factor (IRF) family IRF3 and IRF7 are the major modulators of IFN gene expression (Hemmi H et al. 2004). Activation of IRF3 and IRF7, which is mediated by TBK1/IKK protein kinases, promotes IFN gene expression and the production of IFN developing an effective antiviral immune response (Hemmi H et al. 2004).Irf-3 deficient mice were found to be more vulnerable to virus infection. Mouse cells defective in IRF3 and IRF7 expression totally fail to induce IFN genes in response to viral infection. It was shown on mice and mouse cells that both IRF3 and IRF7 have non redundant and distinct roles (Sato M et al. 2000). IRF3 is expressed at a basal level in normally growing cells and is a major factor in the early induction phase of IFN-alpha/beta production, while the IRF7 gene expression is induced upon IFNs stimulation and IRF7 is involved in the late induction phase. SH2-containing protein tyrosine phosphatase 2 (SHP-2) has been shown to inhibit the TRIF-dependent production of proinflammatory cytokines and type I interferon in LPS or poly(I-C)-stimulated mouse peritoneal macrophages. SHP-2 overexpression also inhibited TRIF-induced IFN-luciferase reporter gene expression in human embryonic kidney HEK293 cells. Experiments with truncated SHP-2 or truncated TBK1 mutants revealed that C-terminal domain of SHP-2 associates with N-terminal domain of TBK1 when coexpressed in HEK293 cells. Furthermore, SHP-2 is thought to prevent TBK1-mediated downstream substrate phosphorylation in tyrosine phosphatase activity independent manner by binding to kinase domain of TBK1 (An H et al. 2006).

Authored: de Bono, B, 2005-08-16 10:54:15Reviewed: Gay, NJ, 2006-04-24 16:48:17Reviewed: Gillespie, ME, 2010-11-30Reviewed: Fitzgerald, Katherine A, 2012-11-13Reviewed: Masci, Anna Maria, 2014-05-16Edited: Shamovsky, V, 2014-05-16

Reactome DB_ID: 9013982

Converted from EntitySet in Reactome

Reactome DB_ID: 450317

IRF3,IRF7 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityIRF7 [cytosol]IRF3 [cytosol]

UniProtQ92985UniProtQ14653

Reactome DB_ID: 9013981

activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7 [endosome membrane]

activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7

Reactome DB_ID: 9013982

Converted from EntitySet in Reactome

Reactome DB_ID: 450317

Reactome Database ID Release 709013981Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013981ReactomeR-HSA-9013981

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013981.2Reactome Database ID Release 709013979Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013979ReactomeR-HSA-9013979

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013979.214703513Pubmed2004Identification of Ser-386 of interferon regulatory factor 3 as criticalMori, MYoneyama, MIto, TTakahashi, KInagaki, FFujita, ToshiroJ Biol Chem 279:9698-70211070172Pubmed2000Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene inductionSato, MSuemori, HHata, NAsagiri, MOgasawara, KNakao, KNakaya, TKatsuki, MNoguchi, STanaka, NTaniguchi, TImmunity 13:539-489566918Pubmed1998Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradationLin, RHeylbroeck, CPitha-Rowe, Paula MHiscott, JMol Cell Biol 18:2986-9617157040Pubmed2006SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine productionAn, HuazhangZhao, WHou, JinZhang, YXie, YunZheng, YuejuanXu, HongmeiQian, ChengZhou, JunYu, YizhiLiu, ShuxunFeng, GCao, XImmunity 25:919-28

2.7.11

Phosphorylation of IRF-3/IRF7 and their release from the activated TLR3 complex

Human IRF3 is activated through a two step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi. It requires Ser386 and/or Ser385 (site 1) and a cluster of serine/threonine residues between Ser396 and Ser405 (site 2) (Panne et al. 2007). Phosphorylated residues at site 2 alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1. Phosphorylation at site 1 is required for IRF3 dimerization.IRF3 and IRF7 transcription factors possess distinct structural characteristics; IRF7 is phosphorylated on Ser477 and Ser479 residues (Lin R et al. 2000). TRAF6 mediated ubiquitination of IRF7 is also required and essential for IRF7 phosphorylation and activation. The K-63 linked ubiquitination occurs on the last three C-terminal lysine sites (positions 444, 446, and 452) of human IRF7 independently of its C-terminal functional phosphorylation sites.(Ning et al. 2008).

Reactome DB_ID: 113592

Reactome DB_ID: 9013981

Reactome DB_ID: 9013982

Converted from EntitySet in Reactome

Reactome DB_ID: 450240

p-4S,T404-IRF3,p-S477,S479-IRF7 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-4S,T404-IRF3 [cytosol]p-S477,S479-IRF7 [cytosol]

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9013981

GO0004674

GO molecular function

Reactome Database ID Release 709013988Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013988Reactome Database ID Release 709013978Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013978ReactomeR-HSA-9013978

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013978.218710948Pubmed2008TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1Ning, SCampos, ADDarnay, BGBentz, GLPagano, JSMol Cell Biol 28:6536-4617526488Pubmed2007Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switchPanne, DMcWhirter, SMManiatis, THarrison, SCJ Biol Chem 282:22816-2210893229Pubmed2000Multiple regulatory domains control IRF-7 activity in response to virus infectionLin, RMamane, YHiscott, JJ Biol Chem 275:34320-7

Dimerization of phosphorylated IRF3/IRF7

Phosphorylation results in IRF-3 dimerization and removal of an autoinhibitory structure to allow interaction with the coactivators CBP/p300.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gay, NJ, 2006-04-24 16:48:17Reviewed: Gillespie, ME, 2010-11-30Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2011-08-12

Converted from EntitySet in Reactome

Reactome DB_ID: 450240

Converted from EntitySet in Reactome

Reactome DB_ID: 450256

phosphorylated IRF3 and/or IRF7 dimer [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 70168933Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168933ReactomeR-HSA-168933

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168933.114555995Pubmed2003X-ray crystal structure of IRF-3 and its functional implicationsTakahasi, KSuzuki, NNHoriuchi, MMori, MSuhara, WOkabe, YFukuhara, YTerasawa, HAkira, ShizuoFujita, TInagaki, FNat Struct Biol 10:922-7

Dimerized phospho-IRF3/IRF7 is transported to the nucleus

IRF3-P:IRF3-P' is translocated from cytosol to nucleoplasm.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gay, NJ, 2006-04-24 16:48:17Reviewed: Gillespie, ME, 2010-11-30Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2011-08-12

Converted from EntitySet in Reactome

Reactome DB_ID: 450256

Converted from EntitySet in Reactome

Reactome DB_ID: 450349

nucleoplasmGO0005654

phosphorylated IRF3 and/or IRF7 dimer [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 70177671Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177671ReactomeR-HSA-177671

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177671.1

Reactome Database ID Release 709013973Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013973ReactomeR-HSA-9013973

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013973.217332413Pubmed2007Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunityTenoever, BRNg, SLChua, MAMcWhirter, SMGarcia-Sastre, AManiatis, TScience 315:1274-815502848Pubmed2004Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signalingSarkar, SNPeters, KLElco, CPSakamoto, SPal, SSen, GCNat Struct Mol Biol 11:1060-714679297Pubmed2004IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblastsMcWhirter, SMFitzgerald, Katherine ARosains, JRowe, DCGolenbock, DTManiatis, TProc Natl Acad Sci U S A 101:233-8GO0035666

GO biological process

TICAM1, RIP1-mediated IKK complex recruitment

Receptor-interacting protein 1 (RIP1) mediates the activation of interferon-alpha/beta via intermediate activation of IKK/TBK1 or NFkB pathways.

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gay, NJ, 2006-04-24 16:48:17Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2009-12-16

Viral dsRNA:TLR3:TRIF complex recruits RIP1

RIP1 is recruited to the activated TLR receptor by binding to TICAM1(TRIF) via its RHIM motif, followed by its polyubiquitination. Polyubiquitination is possibly mediated by TRAF6 that is also recruited to TICAM1 (Cusson-Hermance N et al. 2005). Other E3-ubiquitin ligases - cIAP1 and cIAP2 - have been reported to promote polyubiquitination of RIP proteins (Bertrand MJM et al. 2011). RIP3 was shown to inhibit TRIF-induced NFkB activation in dose-dependent manner when overexpressed in HEK293T cells by competing with TRIF to bind RIP1 (Meylan E et al. 2004).

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gay, NJ, 2006-04-24 16:48:17Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 168651

UniProt:Q13546 RIPK1

RIPK1

RIPRIPK1RIP1FUNCTION Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage (PubMed:11101870, PubMed:17389591, PubMed:19524512, PubMed:19524513). Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor (PubMed:11101870, PubMed:17389591, PubMed:19524512, PubMed:19524513). Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:17389591). Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules (PubMed:15258597). Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death (PubMed:15258597). RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex (PubMed:19524513, PubMed:19524512).ACTIVITY REGULATION Serine-threonine kinase activity is inhibited by linear polyubiquitination ('Met-1'-linked) by the LUBAC complex (By similarity). Inhibited by necrostatins, including necrostatin-1, necrostatin-3 and necrostatin-4 (PubMed:23473668).SUBUNIT Interacts (via RIP homotypic interaction motif) with RIPK3 (via RIP homotypic interaction motif) (PubMed:11734559, PubMed:29883609, PubMed:19524512, PubMed:10358032). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity (PubMed:22265414). Interacts (via the death domain) with TNFRSF6 (via the death domain) and TRADD (via the death domain) (PubMed:8612133). Is recruited by TRADD to TNFRSF1A in a TNF-dependent process (PubMed:24130170). Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and TRAF3 (PubMed:8612133, PubMed:9927690, PubMed:11854271, PubMed:11116146). Interacts with BNLF1 (PubMed:10409763). Interacts with SQSTM1 upon TNF-alpha stimulation (PubMed:10356400). May interact with MAVS/IPS1 (PubMed:16127453). Interacts with ZFAND5 (PubMed:14754897). Interacts with RBCK1 (PubMed:17449468). Interacts with ZBP1 (By similarity). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4 (PubMed:21931591). Interacts (via kinase domain) with DAB2IP (via Ras-GAP domain); the interaction occurs in a TNF-alpha-dependent manner (PubMed:17389591). Interacts with ARHGEF2 (PubMed:21887730). Interacts (via protein kinase domain) with RFFL; involved in RIPK1 ubiquitination (PubMed:18450452). Interacts with RNF34; involved in RIPK1 ubiquitination (Ref.33). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with PELI1 (PubMed:29883609). Interacts (via Death domain) with CRADD (via Death domain); the interaction is direct (PubMed:9044836).SUBUNIT (Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation.SUBUNIT (Microbial infection) Interacts with Murid herpesvirus 1 protein RIR1.DOMAIN Contains a C-terminal death domain (DD) that engages other DD-containing proteins as well as a central (intermediate) region important for NF-kB activation and RHIM-dependent signaling (PubMed:10356400). The Death domain mediates a direct interaction with the Death domain of CRADD (PubMed:9044836).PTM Proteolytically cleaved by caspase-8 during TNF-induced apoptosis (PubMed:10521396). Cleavage abolishes NF-kappa-B activation and enhances pro-apoptotic signaling through the TRADD-FADD interaction (PubMed:10521396).PTM RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:18408713, PubMed:19524513). Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex (PubMed:18408713).PTM Ubiquitinated by 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin (PubMed:15258597, PubMed:16603398, PubMed:18450452, PubMed:21455173, PubMed:21931591, PubMed:29883609, Ref.33). Polyubiquitination with 'Lys-63'-linked chains by TRAF2 induces association with the IKK complex (PubMed:15258597). Deubiquitination of 'Lys-63'-linked chains and polyubiquitination with 'Lys-48'-linked chains by TNFAIP3 leads to RIPK1 proteasomal degradation and consequently down-regulates TNF-alpha-induced NFkappa-B signaling (PubMed:15258597). 'Lys-48'-linked polyubiquitination by RFFL or RNF34 also promotes proteasomal degradation and negatively regulates TNF-alpha-induced NF-kappa-B signaling (PubMed:18450452, Ref.33). Linear polyubiquitinated; the head-to-tail linear polyubiquitination ('Met-1'-linked) is mediated by the LUBAC complex and decreases protein kinase activity (PubMed:21455173). Deubiquitination of linear polyubiquitin by CYLD promotes the kinase activity (By similarity). Also ubiquitinated with 'Lys-11'-linked chains (PubMed:21455173). Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B (PubMed:21931591). Ubiquitinated with 'Lys-63'-linked chains by PELI1 (PubMed:29883609).SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

UniProtQ13546

EQUAL

671

EQUAL

Reactome DB_ID: 168907

Reactome DB_ID: 177649

viral dsRNA:TLR3:TICAM1:RIPK1 [endosome membrane]

viral dsRNA:TLR3:TICAM1:RIPK1

viral dsRNA:TLR3:TRIF:RIP1

Reactome DB_ID: 450326

EQUAL

671

EQUAL

Reactome DB_ID: 168907

Reactome Database ID Release 70177649Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177649ReactomeR-HSA-177649

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177649.3Reactome Database ID Release 70168930Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168930ReactomeR-HSA-168930

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168930.416246838Pubmed2005NF-kappaB protects macrophages from lipopolysaccharide-induced cell death: the role of caspase 8 and receptor-interacting proteinMa, YTemkin, VLiu, HPope, RMJ Biol Chem 280:41827-3421931591Pubmed2011cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4)Bertrand, Mathieu J MLippens, SaskiaStaes, AnGilbert, BarbaraRoelandt, RiaDe Medts, JelleGevaert, KrisDeclercq, WimVandenabeele, PPLoS ONE 6:e2235615064760Pubmed2004RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa BMeylan, EBurns, KHofmann, KBlancheteau, VMartinon, FKelliher, MTschopp, JürgNat Immunol 5:503-715814722Pubmed2005Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motifKaiser, WJOffermann, MKJ Immunol 174:4942-5216115877Pubmed2005Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activationCusson-Hermance, NKhurana, SLee, THFitzgerald, Katherine AKelliher, MAJ Biol Chem 280:36560-6

INHIBITION

Reactome Database ID Release 70450301Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450301ReactomeR-HSA-450301

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450301.1

Reactome DB_ID: 450328

UniProt:Q9Y572 RIPK3

RIPK3

RIPK3RIP3FUNCTION Essential for necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 and MLKL to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production.SUBUNIT Interacts (via RIP homotypic interaction motif) with RIPK1 (via RIP homotypic interaction motif); this interaction induces RIPK1 phosphorylation and formation of a RIPK1-RIPK3 necrosis-inducing complex. Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity. Interacts with MLKL; the interaction is direct. Binds TRAF2 and is recruited to the TNFR-1 signaling complex. Interacts with PYGL, GLUL and GLUD1; these interactions result in activation of these metabolic enzymes. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with ARHGEF2. Interacts with PELI1 (via atypical FHA domain); the phosphorylated form at Thr-182 binds preferentially to PELI1 (PubMed:29883609). Interacts with BUB1B, TRAF2 and STUB1 (PubMed:29883609). Interacts with ZBP1 (By similarity).TISSUE SPECIFICITY Highly expressed in the pancreas. Detected at lower levels in heart, placenta, lung and kidney. Isoform 3 is significantly increased in colon and lung cancers.PTM RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Phosphorylation of Ser-199 plays a role in the necroptotic function of RIPK3. Phosphorylation at Ser-227 is required for binding MLKL (PubMed:11734559, PubMed:19524512, PubMed:22265413). Phosphorylation at Thr-182 is important for its kinase activity, interaction with PELI1 and PELI1-mediated 'Lys-48'-linked polyubiquitination and for its ability to mediate TNF-induced necroptosis (PubMed:29883609).PTM Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B (PubMed:21931591). Polyubiquitinated with 'Lys-48'-linked chains by PELI1 leading to its subsequent proteasome-dependent degradation. Ubiquitinated by STUB1 leading to its subsequent proteasome-dependent degradation (PubMed:29883609).SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

UniProtQ9Y572

EQUAL

518

EQUAL

6.3.2.19

K63-linked ubiquitination of RIP1 bound to the activated TLR complex

RIP1 polyubiquitination was induced upon TNF- or poly(I-C) treatment of the macrophage cell line RAW264.7 and the U373 astrocytoma line (Cusson-Hermance et al 2005). These workers have suggested that RIP1 may use similar mechanisms to induce NF-kB in the TNFR1- and Trif-dependent TLR pathways.RIP1 modification with Lys-63 polyubiquitin chains was shown to be essential for TNF-induced activation of NF-kB (Ea et al. 2006). It is thought that TRAF family members mediate this Lys63-linked ubiquitination of RIP1 (Wertz et al. 2004, Tada et al 2001, Vallabhapurapu and Karin 2009), which may facilitate recruitment of the TAK1 complex and thus activation of NF-kB. Binding of NEMO to Lys63-linked polyubiquitinated RIP1 is also required in the signaling cascade from the activated receptor to the IKK-mediated NF-kB activation (Wu et al. 2006).

Authored: de Bono, B, 2005-08-16 10:54:15Reviewed: Gay, NJ, 2006-04-24 16:48:17Reviewed: Gillespie, ME, 2010-11-30Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2011-08-12

Reactome DB_ID: 450152

K63polyUb [cytosol]

K63polyUb

K63-polyubiquitinLys-63 polyubiquitin

Reactome DB_ID: 177649

Reactome DB_ID: 9014344

activated TLR3:TICAM1:K63pUb-RIP1 [endosome membrane]

activated TLR3:TICAM1:K63pUb-RIP1

viral dsRNA:TLR3:TICAM1:K63pUb-RIP1

Reactome DB_ID: 937021

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 377

377

EQUAL

671

EQUAL

Reactome DB_ID: 168907

Reactome Database ID Release 709014344Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014344ReactomeR-HSA-9014344

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014344.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 2569050

RIP1 ubiqutin ligases [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 702569080Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2569080Reactome Database ID Release 709014342Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014342ReactomeR-HSA-9014342

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014342.216547522Pubmed2006Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]Wu, CJConze, DBLi, TSrinivasula, SMAshwell, JDNat Cell Biol 8:398-40611479302Pubmed2001Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell deathTada, KeiyaOkazaki, TSakon, SKobarai, TKurosawa, KYamaoka, SHashimoto, HMak, TWYagita, HOkumura, KYeh, WCNakano, HJ Biol Chem 276:36530-415258597Pubmed2004De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signallingWertz, IEO'Rourke, KMZhou, HEby, MAravind, LSeshagiri, SWu, PWiesmann, CBaker, RBoone, DLMa, AKoonin, EVDixit, VMNature 430:694-916603398Pubmed2006Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMOEa, CKDeng, LXia, ZPPineda, GChen, ZJMol Cell 22:245-57

IKBKG subunit of IKK complex binds K63pUb- RIP1 within the TLR3 complex

Nemo subunit of IKK complex binds polyubiquinated RIP1Structural studies showed that NEMO binds both Lys-63- and linear polyubiquitin chains,both critical for NF-kB activation.

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-11-30Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2011-08-12

Reactome DB_ID: 168113

CHUK:IKBKB:IKBKG [cytosol]

CHUK:IKBKB:IKBKG

IKKA:IKBKB:IKBKGIKK complexInhibitor of KappaB kinase (IKK) Complex

Reactome DB_ID: 168114

UniProt:O14920 IKBKB

IKBKB

IKBKBIKKBFUNCTION Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:30337470). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation. Phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation.SUBUNIT Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Interacts with SQSTM1 through PRKCZ or PRKCI (PubMed:10356400). Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6 (By similarity). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with NALP2 (PubMed:15456791). Interacts with TICAM1 (PubMed:14739303). Interacts with FAF1; the interaction disrupts the IKK complex formation (PubMed:17684021). Interacts with ATM (PubMed:16497931). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with NIBP; the interaction is direct (PubMed:15951441). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with TRIM21 (PubMed:19675099). Interacts with NLRC5; prevents IKBKB phosphorylation and kinase activity (PubMed:20434986). Interacts with PDPK1 (PubMed:16207722). Interacts with EIF2AK2/PKR (PubMed:10848580). The phosphorylated form interacts with PPM1A and PPM1B (PubMed:18930133). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with IKBKE (PubMed:23453969). Interacts with NAA10, leading to NAA10 degradation (PubMed:19716809). Interacts with FOXO3 (PubMed:15084260). Interacts with AKAP13 (PubMed:23090968). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14; disrupts IKBKB-IKBKG interaction preventing I-kappa-B-kinase (IKK) core complex formation and leading to a decrease of IKBKB phosphorylation and NF-kappaB activation (PubMed:27426725).SUBUNIT (Microbial infection) Interacts with Yersinia yopJ.SUBUNIT (Microbial infection) Interacts with vaccinia virus protein B14.TISSUE SPECIFICITY Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood.DOMAIN The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.PTM Upon cytokine stimulation, phosphorylated on Ser-177 and Ser-181 by MEKK1 and/or MAP3K14/NIK as well as TBK1 and PRKCZ; which enhances activity. Once activated, autophosphorylates on the C-terminal serine cluster; which decreases activity and prevents prolonged activation of the inflammatory response. Phosphorylated by the IKK-related kinases TBK1 and IKBKE, which is associated with reduced CHUK/IKKA and IKBKB activity and NF-kappa-B-dependent gene transcription. Dephosphorylated at Ser-177 and Ser-181 by PPM1A and PPM1B.PTM (Microbial infection) Acetylation of Thr-180 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the I-kappa-B pathway.PTM Ubiquitinated. Monoubiquitination involves TRIM21 that leads to inhibition of Tax-induced NF-kappa-B signaling. According to PubMed:19675099, 'Ser-163' does not serve as a monoubiquitination site. According to PubMed:16267042, ubiquitination on 'Ser-163' modulates phosphorylation on C-terminal serine residues.PTM (Microbial infection) Monoubiquitination by TRIM21 is disrupted by Yersinia yopJ.PTM Hydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappa-B.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.

UniProtO14920

EQUAL

756

EQUAL

Reactome DB_ID: 168104

UniProt:O15111 CHUK

CHUK

TCF16CHUKIKKAFUNCTION Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260).ACTIVITY REGULATION Activated when phosphorylated and inactivated when dephosphorylated.SUBUNIT Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:10195894, PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Directly interacts with TRPC4AP (By similarity). May interact with TRAF2 (PubMed:19150425). Interacts with NALP2 (PubMed:15456791). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity (PubMed:20434986). Interacts with PIAS1; this interaction induces PIAS1 phosphorylation (PubMed:17540171). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with FOXO3 (PubMed:15084260). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14 (PubMed:27426725).SUBUNIT (Microbial infection) Interacts with InlC of Listeria monocytogenes.TISSUE SPECIFICITY Widely expressed.DOMAIN The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.PTM Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.PTM (Microbial infection) Acetylation of Thr-179 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.

UniProtO15111

EQUAL

745

EQUAL

Reactome DB_ID: 168108

UniProt:Q9Y6K9 IKBKG

IKBKG

FIP3IKBKGNEMOFUNCTION Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. Its binding to scaffolding polyubiquitin seems to play a role in IKK activation by multiple signaling receptor pathways. However, the specific type of polyubiquitin recognized upon cell stimulation (either 'Lys-63'-linked or linear polyubiquitin) and its functional importance is reported conflictingly. Also considered to be a mediator for TAX activation of NF-kappa-B. Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity. Essential for viral activation of IRF3. Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination.SUBUNIT Homodimer; disulfide-linked. Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex. The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65. Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP. Interacts with COPS3, CYLD, NALP2, TRPC4AP and PIDD1. Interacts with ATM; the complex is exported from the nucleus. Interacts with TRAF6. Interacts with IKBKE. Interacts with TANK; the interaction is enhanced by IKBKE and TBK1. Part of a ternary complex consisting of TANK, IKBKB and IKBKG. Interacts with ZFAND5. Interacts with RIPK2. Interacts with TNIP1 and TNFAIP3; TNIP1 facilitates the TNFAIP3-mediated de-ubiquitination of IKBKG. Interacts with TNFAIP3; the interaction is induced by TNF stimulation and by polyubiquitin. Binds polyubiquitin; the interaction is mediated by two domains; reports about the binding to 'Lys-63'-linked and/or linear polyubiquitin, respective binding affinities and stoichiometry are conflicting. Interacts with NLRP10. Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with TRIM29; this interaction induces IKBKG/NEMO ubiquitination and proteolytic degradation (PubMed:27695001). Interacts with TRIM13; this interaction leads to IKBKG/NEMO ubiquitination (PubMed:25152375).SUBUNIT (Microbial infection) Interacts with Molluscum contagiosum virus protein MC005; this interaction inhibits NF-kappa-B activation.SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax oncoprotein; the interaction activates IKBKG.SUBUNIT (Microbial infection) Interacts with Shigella flexneri ipah9.8; the interaction promotes TNIP1-dependent 'Lys-27'-linked polyubiquitination of IKBKG which perturbs NF-kappa-B activation during bacterial infection.TISSUE SPECIFICITY Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The leucine-zipper domain and the CCHC NOA-type zinc-finger are essential for polyubiquitin binding and for the activation of IRF3.PTM Phosphorylation at Ser-68 attenuates aminoterminal homodimerization.PTM Polyubiquitinated on Lys-285 through 'Lys-63'; the ubiquitination is mediated by NOD2 and RIPK2 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Polyubiquitinated on Lys-399 through 'Lys-63'; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Monoubiquitinated on Lys-277 and Lys-309; promotes nuclear export. Polyubiquitinated through 'Lys-27' by TRIM23; involved in antiviral innate and inflammatory responses. Linear polyubiquitinated on Lys-111, Lys-143, Lys-226, Lys-246, Lys-264, Lys-277, Lys-285, Lys-292, Lys-302, Lys-309 and Lys-326; the head-to-tail polyubiquitination is mediated by the LUBAC complex and plays a key role in NF-kappa-B activation. Deubiquitinated by USP10 in a TANK-dependent and -independent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage (PubMed:25861989).PTM Sumoylated on Lys-277 and Lys-309 with SUMO1; the modification results in phosphorylation of Ser-85 by ATM leading to a replacement of the sumoylation by mono-ubiquitination on these residues.PTM Neddylated by TRIM40, resulting in stabilization of NFKBIA and down-regulation of NF-kappa-B activity.PTM (Microbial infection) Cleaved by hepatitis A virus (HAV) protease 3C allowing the virus to disrupt the host innate immune signaling.PTM (Microbial infection) Polyubiquitinated on Lys-309 and Lys-321 via 'Lys-27'-linked ubiquitin by Shigella flexneri E3 ubiquitin-protein ligase ipah9.8, leading to its degradation by the proteasome.

UniProtQ9Y6K9

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Reactome Database ID Release 70168113Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168113ReactomeR-HSA-168113

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168113.3

Reactome DB_ID: 9014344

Reactome DB_ID: 9014341

viral dsRNA:TLR3:TICAM1:K63pUb-RIP1:CHUK:IKBKB:IKBKG [endosome membrane]

viral dsRNA:TLR3:TICAM1:K63pUb-RIP1:CHUK:IKBKB:IKBKG

viral dsRNA:TLR3:TICAM1:K63pUb-RIP1:IKK complex

Reactome DB_ID: 168113

Reactome DB_ID: 9014344

Reactome Database ID Release 709014341Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014341ReactomeR-HSA-9014341

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014341.2Reactome Database ID Release 709014343Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014343ReactomeR-HSA-9014343

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014343.219303852Pubmed2009Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activationRahighi, SIkeda, FKawasaki, MAkutsu, MSuzuki, NKato, RKensche, TUejima, TBloor, SKomander, DRandow, FWakatsuki, SDikic, ICell 136:1098-10919185524Pubmed2009Structural basis for recognition of diubiquitins by NEMOLo, YCLin, SCRospigliosi, CCConze, DBWu, CJAshwell, JDEliezer, DWu, HMol Cell 33:602-15

Reactome Database ID Release 70168927Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168927ReactomeR-HSA-168927

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168927.3GO0002756

GO biological process

TLR3-mediated TICAM1-dependent programmed cell death

TLR3 and TLR4 trigger TRIF(TICAM1)-dependent programmed cell death in various human and mouse cells (Kalai M et al. 2002; Han KJ et al. 2004; Kaiser WJ and Offermann MK 2005; Estornes Y et al. 2012; He S et al. 2011). Apoptosis is a prevalent form of programmed cell death and is mediated by the activation of a set of caspases. In addition to apoptosis, TLR3/TLR4 activation induces RIP3-dependent necroptosis. These two programmed cell-death pathways may suppress each other. When the caspase activity is impaired or inhibited, certain cell types switch the apoptotic death program to necroptosis in response to various stimuli (TNF, Fas, viral infection and other stress stimuli) (Kalai M et al. 2002; Weber A et al. 2010; Feoktistova M et al. 2011, Tenev et al 2011).

Authored: Shamovsky, V, 2012-05-15Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2012-11-19

TLR3-induced ripoptosome assembly

TRIF (also known as TICAM1) was repored to efficiently induce apoptosis when overexpressed in human HEK293T cells. TRIF-induced apoptosis occurred through activation of the FADD-caspase-8 axis (Kaiser WJ and Offermann MK 2005; Kalai M et al. 2002; Estornes Y et al. 2012). C-terminus of TRIF was shown to form complexes with both RIP1 and RIP3, and disruption of these interactions by mutating the RHIM eliminated the ability of TRIF to induce apoptosis (Kaiser WJ and Offermann MK 2005). Prevention of RIP1 ubiquitination leads to a strong association of RIP1 and caspase-8 (Feoktistova M et al. 2011, Tenev et al. 2011).

Authored: Shamovsky, V, 2012-05-15Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2012-11-19

Reactome DB_ID: 54639

UniProt:Q13158 FADD

FADD

FADDMORT1GIG3FUNCTION Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation. Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis. Involved in interferon-mediated antiviral immune response, playing a role in the positive regulation of interferon signaling.SUBUNIT Can self-associate. Interacts with CFLAR, PEA15 and MBD4. When phosphorylated, part of a complex containing HIPK3 and FAS. May interact with MAVS/IPS1. Interacts with MOCV v-CFLAR protein and PIDD1. Interacts (via death domain) with FAS (via death domain). Interacts with CASP8. Interacts directly (via DED domain) with NOL3 (via CARD domain); inhibits death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation (By similarity).SUBUNIT (Microbial infection) Interacts with human papillomavirus 16/HPV16 protein E6.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus proteins MC159L/v-CFLAR and MC160L.TISSUE SPECIFICITY Expressed in a wide variety of tissues, except for peripheral blood mononuclear leukocytes.DOMAIN Contains a death domain involved in the binding of the corresponding domain within Fas receptor.DOMAIN The interaction between the FAS and FADD death domains is crucial for the formation of the death-inducing signaling complex (DISC).

UniProtQ13158

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Reactome DB_ID: 57031

UniProt:Q14790 CASP8

CASP8

CASP8MCH5FUNCTION Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex.ACTIVITY REGULATION Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis.SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit (PubMed:10508784). Interacts with FADD, CFLAR and PEA15 (PubMed:10442631). Isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1 (PubMed:11917123, PubMed:9334338). Interacts with TNFAIP8L2 (By similarity). Interacts with CASP8AP2 (PubMed:16378960). Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation (PubMed:15069192). Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium (PubMed:15509781). Interacts with UBR2 (PubMed:28602583).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation.SUBUNIT (Microbial infection) Interacts with NleF from pathogenic E.coli.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus protein MC160.TISSUE SPECIFICITY Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle.DOMAIN Isoform 9 contains a N-terminal extension that is required for interaction with the BCAP31 complex.PTM Generation of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events.PTM Phosphorylation on Ser-387 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes.POLYMORPHISM Genetic variations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic variations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner.SIMILARITY Belongs to the peptidase C14A family.

UniProtQ14790

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Reactome DB_ID: 177649

Reactome DB_ID: 9013891

activated TLR3:TRIF:RIP1:FADD:pro-caspase-8 [endosome membrane]

activated TLR3:TRIF:RIP1:FADD:pro-caspase-8

Reactome DB_ID: 54639

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Reactome DB_ID: 168651

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Reactome DB_ID: 168907

Reactome DB_ID: 57031

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Reactome Database ID Release 709013891Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013891ReactomeR-HSA-9013891

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013891.2Reactome Database ID Release 709013889Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013889ReactomeR-HSA-9013889

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013889.212752666Pubmed2003Caspase-activation pathways in apoptosis and immunityCreagh, EMConroy, HMartin, SJImmunol Rev 193:10-2114739303Pubmed2004Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathwaysHan, Ke-JunSu, XiaoqinXu, Liang-GuoBin, Liang-HuaZhang, JunShu, Hong-BingJ. Biol. Chem. 279:15652-6121737330Pubmed2011cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoformsFeoktistova, MariaGeserick, PeterKellert, BeateDimitrova, Diana PanayotovaLanglais, ClaudiaHupe, MikeCain, KelvinMacFarlane, MarionHäcker, GeorgLeverkus, MartinMol. Cell 43:449-6312181749Pubmed2002Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNAKalai, MVan Loo, GVanden Berghe, TMeeus, ABurm, WSaelens, XVandenabeele, PCell Death Differ. 9:981-9422421964Pubmed2012dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8Estornes, YToscano, FVirard, FJacquemin, GPierrot, AVanbervliet, BBonnin, MLalaoui, NMercier-Gouy, PPachéco, YSalaun, BRenno, TMicheau, OLebecque, SCell Death Differ. 19:1482-9421737329Pubmed2011The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPsTenev, TenchoBianchi, KatiusciaDarding, MauriceBroemer, MeikeLanglais, ClaudiaWallberg, FredrikZachariou, AnnaLopez, JuanitaMacFarlane, MarionCain, KelvinMeier, PascalMol. Cell 43:432-48

3.4.22

Caspase-8 processing within TLR3 complex

TLR3 and TLR4 were shown to mediate apoptosis in various human cell lines in the FADD:caspasse-8-dependent manner (Kalai M et al. 2002; Kaiser WJ and Offermann MK 2005; Estornes Y et al. 2012). Caspase-8 zymogens (procaspase-8) are present in the cells as inactive monomers, containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domains separated by a smaller linker region (Donepudi M et al. 2003; Keller N et al. 2009). Dimerization is required for caspase-8 activation (Donepudi M et al. 2003). The dimerization event occurs at the receptor signaling complex. Once dimerized, caspase-8 zymogen undergoes a series of autoproteolytic cleavage events at aspartic acid residues in their interdomain linker regions. A second cleavage event between the the N-terminal prodomain and the catalytic domain releases the active caspase from the activation complex into the cytosol. The resulting fully active enzyme is a homodimer of catalytic domains, where each domain is compsed of a large p18 and a small p10 subunit (Keller N et al. 2009; Oberst A et al. 2010).

Authored: Shamovsky, V, 2012-05-15Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2012-11-19

Reactome DB_ID: 9013891

Reactome DB_ID: 9013893

activated TLR3:TRIF:RIP1:FADD [endosome membrane]

activated TLR3:TRIF:RIP1:FADD

Reactome DB_ID: 54639

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Reactome DB_ID: 168907

Reactome Database ID Release 709013893Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013893ReactomeR-HSA-9013893

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013893.2

Reactome DB_ID: 2562550

active caspase-8 [cytosol]

active caspase-8

Reactome DB_ID: 139950

Caspase-8 dimer [cytosol]

Caspase-8 dimer

Reactome DB_ID: 76158

385

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Reactome DB_ID: 75975

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Reactome Database ID Release 70139950Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=139950ReactomeR-HSA-139950

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-139950.1Reactome Database ID Release 702562550Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2562550ReactomeR-HSA-2562550

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2562550.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9013891

GO0004197

GO molecular function

Reactome Database ID Release 709013890Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013890Reactome Database ID Release 709013895Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013895ReactomeR-HSA-9013895

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013895.219278658Pubmed2009Structural and biochemical studies on procaspase-8: new insights on initiator caspase activationKeller, NMares, JZerbe, OGrütter, MGStructure 17:438-4812620240Pubmed2003Insights into the regulatory mechanism for caspase-8 activationDonepudi, MrudulaMac Sweeney, AengusBriand, ChristopheGrütter, Markus GMol. Cell 11:543-920308068Pubmed2010Inducible dimerization and inducible cleavage reveal a requirement for both processes in caspase-8 activationOberst, APop, CristinaTremblay, AGBlais, VDenault, JBSalvesen, Guy S.Green, DRJ Biol Chem 285:16632-42GO0097190

GO biological process

RIP3 binds TICAM1 within TLR3 complex to mediate necroptosis

TLR3 and TLR4 -directed programmed necrosis (necroptosis) is mediated by the TRIF-RIP3 pathway in mouse macrophages [He S e al 2011]. RIP3 was shown to be essential mediator in TLR3-induced necroptotic cell death in human epithelial cell lines. Knockdown of RIP3 in human keratinocyte HaCaT cells blocked TLR3-mediated necroptosis without affecting the apoptotic response. Moreover, overexpression of RIP3 in human epithelial carcinoma cell line HeLa led to increased caspase-independent TLR3-induced cell death in the absence of IAPs [Feoktistova M et al 2011]. In addition, in caspase-8- or FADD-deficient human Jurkat cells dsRNA induced programmed necrosis, instead of apoptosis [Kalai M et al 2002]. Thus, when caspase-dependent apoptosis is inhibited or absent, the alternative RIP3-mediated programmed cell death is induced.

Authored: Shamovsky, V, 2012-05-15Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2012-11-19

Reactome DB_ID: 450328

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Converted from EntitySet in Reactome

Reactome DB_ID: 9013962

TICAM1:activated TLR3 complexes [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Converted from EntitySet in Reactome

Reactome DB_ID: 9013956

RIP3:TICAM1:activated TLR3 [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 709013963Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013963ReactomeR-HSA-9013963

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013963.222123964Pubmed2011Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathwayHe, SudanLiang, YuqiongShao, FengWang, XiaodongProc. Natl. Acad. Sci. U.S.A. 108:20054-9GO0070266

GO biological process

Reactome Database ID Release 709013957Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013957ReactomeR-HSA-9013957

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013957.220019748Pubmed2010Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cellsWeber, AKirejczyk, ZBesch, RPotthoff, SLeverkus, MHäcker, GCell Death Differ. 17:942-51

TICAM1,TRAF6-dependent induction of TAK1 complex

In human, together with ubiquitin-conjugating E2-type enzymes UBC13 and UEV1A (also known as UBE2V1), TRAF6 catalyses Lys63-linked ubiquitination. It is believed that auto polyubiquitination and oligomerization of TRAF6 is followed by binding the ubiquitin receptors of TAB2 or TAB3 (TAK1 binding protein 2 and 3), which stimulates phosphorylation and activation of TGF beta-activated kinase 1(TAK1).TAK1 phosphorylates IKK alpha and IKK beta, which in turn phosphorylate NF-kB inhibitors - IkB and eventually results in IkB degradation and NF-kB translocation to the nucleus. Also TAK1 mediates JNK and p38 MAP kinases activation by phosphorylating MKK4/7 and MKK3/6 respectivly resulting in the activation of many transcription factors. The role of TRAF6 is somewhat controversial and probably cell type specific. TRAF6 autoubiquitination was found to be dispensable for TRAF6 function to activate TAK1 pathway. These findings are consistent with the new mechanism of TRAF6-mediated NF-kB activation that was suggested by Xia et al. (2009). TRAF6 generates unanchored Lys63-linked polyubiquitin chains that bind to the regulatory subunits of TAK1 (TAB2 or TAB3) and IKK(NEMO), leading to the activation of the kinases. Xia et al. (2009) demonstrated in vitro that unlike polyubiquitin chains covalently attached to TRAF6 or IRAK, TAB2 and NEMO-associated ubiquitin chains were found to be unanchored and susceptible to N-terminal ubiquitin cleavage. Only K63-linked polyubiquitin chains, but not monomeric ubiquitin, activated TAK1 in a dose-dependent manner. Optimal activation of the IKK complex was achieved using ubiquitin polymers containing both K48 and K63 linkages.Furthermore, the authors proposed that the TAK1 complexes might be brougt in close proximity by binding several TAB2/3 to a single polyubiquitin chain to facilitate TAK1 kinase trans-phosphorylation. Alternativly, the possibility that polyUb binding promotes allosteric activation of TAK1 complex should be considered (Walsh et al 2008).

Authored: Shamovsky, V, 2010-06-01Reviewed: Gillespie, ME, 2010-11-30Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2010-11-15

Viral dsRNA:TLR3:TICAM1 complex recruits TRAF6

TRAF6 is recruited to the N-terminal domain of TICAM1 and this event is followed by auto polyubiquitination and oligomerization of TRAF6.

Authored: Shamovsky, V, 2009-12-16Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 168907

Reactome DB_ID: 166366

UniProt:Q9Y4K3 TRAF6

TRAF6

TRAF6RNF85FUNCTION E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer. Homooligomer. N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2, IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and PELI3. Binds UBE2V1. Interacts with TAX1BP1. Interacts with ZNF675. Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts with RBCK1. Interacts with TRAF3IP2. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts (via TRAF domains) with WDR34 (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the interaction is required for ERK activation (By similarity). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (PubMed:25861989). Interacts with WDFY3 (By similarity). Interacts with TRIM13 (PubMed:28087809). Interacts with GPS2 (By similarity).TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.PTM Sumoylated on Lys-124, Lys-142 and Lys-453 with SUMO1.PTM Polyubiquitinated on Lys-124; after cell stimulation with IL-1-beta or TGF-beta. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappaB signaling upon DNA damage (PubMed:25861989).SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily.

UniProtQ9Y4K3

EQUAL

522

EQUAL

Reactome DB_ID: 177693

viral dsRNA:TLR3:TRIF:TRAF6 [endosome membrane]

viral dsRNA:TLR3:TRIF:TRAF6

Reactome DB_ID: 168907

Reactome DB_ID: 450272

EQUAL

522

EQUAL

Reactome Database ID Release 70177693Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177693ReactomeR-HSA-177693

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177693.2Reactome Database ID Release 70177694Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177694ReactomeR-HSA-177694

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177694.219112497Pubmed2008TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKLWalsh, MCKim, GKMaurizio, PLMolnar, EEChoi, YPLoS One 3:e406411057907Pubmed2000Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chainDeng, LWang, CSpencer, EYang, LBraun, AYou, JSlaughter, CPickart, CChen, ZJCell 103:351-6120047764Pubmed2010Direct binding of TRAF2 and TRAF6 to TICAM-1/TRIF adaptor participates in activation of the Toll-like receptor 3/4 pathwaySasai, MTatematsu, MOshiumi, HFunami, KMatsumoto, MHatakeyama, SSeya, TMol Immunol

Auto ubiqitination of TRAF6 bound to viral dsRNS:TLR3:TICAM1 complex

TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-03-02Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2010-02-27

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 177693

Reactome DB_ID: 450309

viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6 [endosome membrane]

viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6

Reactome DB_ID: 450227

ubiquitinylated lysine (K63polyUb [endosome membrane]) at 124

124

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522

EQUAL

Reactome DB_ID: 168907

Reactome Database ID Release 70450309Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450309ReactomeR-HSA-450309

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450309.2Reactome Database ID Release 70450259Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450259ReactomeR-HSA-450259

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450259.219675569Pubmed2009Direct activation of protein kinases by unanchored polyubiquitin chainsXia, ZPSun, LChen, XPineda, GJiang, XAdhikari, AZeng, WChen, ZJNature17135271Pubmed2007Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activationLamothe, BBesse, ACampos, ADWebster, WKWu, HDarnay, BGJ Biol Chem 282:4102-12

6.3.2.19

Activated TRAF6 synthesizes unanchored polyubiquitin chains upon TLR3 stimulation

E3 ubiquitin ligase TRAF6 generates free K63 -linked polyubiquitin chains that non-covalently associate with ubiquitin receptors of TAB2/TAB3 regulatory proteins of the TAK1 complex, leading to the activation of the TAK1 kinase.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-03-02Edited: Shamovsky, V, 2010-02-27

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 450152

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 450309

Reactome Database ID Release 701986608Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1986608Reactome Database ID Release 709628444Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9628444ReactomeR-HSA-9628444

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9628444.1

Activated TLR3:TRIF:K63pUb-TRAF6 recruits TAK1complex

TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism.This binding leads to autophosphorylation and activation of TAK1.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gay, NJ, 2006-04-24 16:48:17Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 450152

Reactome DB_ID: 450309

Reactome DB_ID: 450277

TAB1:TAB2,TAB3:TAK1 [cytosol]

TAB1:TAB2,TAB3:TAK1

TRIKA2

Reactome DB_ID: 167923

UniProt:Q15750 TAB1

TAB1

MAP3K7IP1TAB1FUNCTION May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.SUBUNIT Interacts with XIAP and BIRC7 (PubMed:17560374, PubMed:11865055). Interacts with TRAF6 and MAP3K7; during IL-1 signaling (PubMed:8638164, PubMed:10094049, PubMed:11323434). Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (PubMed:11460167).TISSUE SPECIFICITY Ubiquitous.PTM Monoubiquitinated. Deubiquitinated by Y.enterocolitica YopP.CAUTION Lacks several key residues involved in metal-binding and catalytic activity, therefore has lost phosphatase activity.

UniProtQ15750

EQUAL

504

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Reactome DB_ID: 168156

UniProt:O43318 MAP3K7

MAP3K7

TAK1MAP3K7FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity.ACTIVITY REGULATION Activated by proinflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation.SUBUNIT Can form homodimer (PubMed:27426733). Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (PubMed:10838074, PubMed:11460167, PubMed:12242293, PubMed:14670075, PubMed:16289117, PubMed:19675569, PubMed:8638164). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (PubMed:11460167). Interacts with PPM1L and PPM1B/PP2CB (PubMed:11104763). Interaction with PP2A and PPP6C leads to its repressed activity (PubMed:17079228). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (PubMed:10094049, PubMed:12242293). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (PubMed:16893890). Interacts with WDR34 (via WD domains) (PubMed:19521662). Interacts with CYLD and RBCK1 (PubMed:17449468, PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (PubMed:18758450). Interacts with MAPK8IP1 and SMAD6 (By similarity). Interacts with isoform 1 of VRK2 (PubMed:18286207). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (PubMed:15894542). Interacts with TRIM5 (PubMed:21512573). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with PLEKHM1 (via N- and C-terminus) (By similarity). Interacts with TRIM8 (PubMed:22084099). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 2 protein US2; this interaction induces MAP3K7 phosphorylation and subsequent activation.TISSUE SPECIFICITY Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form.PTM Association with TAB1/MAP3K7IP1 promotes autophosphorylation at Ser-192 and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and PPP6C leads to inactivation.PTM 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation. Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (By similarity). Requires 'Lys-63'-linked polyubiquitination for autophosphorylation and subsequent activation. 'Lys-63'-linked ubiquitination does not lead to proteasomal degradation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains. Deubiquitinated by Y.enterocolitica YopP.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

UniProtO43318

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606

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 446874

TAB2,TAB3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTAB3 [cytosol]TAB2 [cytosol]

UniProtQ8N5C8UniProtQ9NYJ8Reactome Database ID Release 70450277Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450277ReactomeR-HSA-450277

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450277.2

Reactome DB_ID: 177689

viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chain [endosome membrane]

viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chain

Converted from EntitySet in Reactome

Reactome DB_ID: 975101

TAB2/3 [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTAB2 [endosome membrane]TAB3 [endosome membrane]

Reactome DB_ID: 450238

EQUAL

504

EQUAL

Reactome DB_ID: 450315

EQUAL

606

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Reactome DB_ID: 450309

Reactome DB_ID: 450271

K63polyUb [endosome membrane]

K63polyUb

K63-polyubiquitinK63 Ligated polyubiquitin Chain

Reactome Database ID Release 70177689Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177689ReactomeR-HSA-177689

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177689.2Reactome Database ID Release 70177690Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177690ReactomeR-HSA-177690

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177690.312609980Pubmed2003Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR Jiang, ZZamanian-Daryoush, MNie, HSilva, AMWilliams, BRLi, XJ Biol Chem 278:16713-917496917Pubmed2007Ubiquitin-mediated activation of TAK1 and IKKAdhikari, AXu, MChen, ZJOncogene 26:3214-2615327770Pubmed2004TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chainsKanayama, ASeth, RBSun, LEa, CKHong, MShaito, AChiu, YHDeng, LChen, ZJMol Cell 15:535-48

2.7.11

Activation of recruited TAK1 within the activated TLR3 complex

TAK1 complex consists of transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004).

Authored: Shamovsky, V, 2009-12-16Reviewed: Gay, NJ, 2006-04-24 16:48:17Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 113592

Reactome DB_ID: 177689

Reactome DB_ID: 177691

viral dsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1 [endosome membrane]

viral dsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1

Reactome DB_ID: 450332

O-phospho-L-threonine at 184

184

EQUAL

O-phospho-L-threonine [MOD:00047]

O-phospho-L-threonine at 187

187

EQUAL

606

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 975101

Reactome DB_ID: 450238

EQUAL

504

EQUAL

Reactome DB_ID: 450309

Reactome DB_ID: 450271

Reactome Database ID Release 70177691Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177691ReactomeR-HSA-177691

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177691.2

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 177689

GO0008349

GO molecular function

Reactome Database ID Release 70450212Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450212Reactome Database ID Release 70177692Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177692ReactomeR-HSA-177692

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177692.216186825Pubmed2005Essential function for the kinase TAK1 in innate and adaptive immune responsesSato, SSanjo, HTakeda, KNinomiya-Tsuji, JYamamoto, MKawai, TMatsumoto, KTakeuchi, OAkira, ShizuoNat Immunol 6:1087-9514633987Pubmed2003Role of the TAB2-related protein TAB3 in IL-1 and TNF signalingIshitani, TTakaesu, GNinomiya-Tsuji, JShibuya, HGaynor, RBMatsumoto, KEMBO J 22:6277-8810702308Pubmed2000TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loopKishimoto, KMatsumoto, KNinomiya-Tsuji, JJ Biol Chem 275:7359-6416260493Pubmed2005TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivoShim, JHXiao, CPaschal, AEBailey, STRao, PHayden, MSLee, KYBussey, CSteckel, MTanaka, NYamada, GAkira, ShizuoMatsumoto, KGhosh, SGenes Dev 19:2668-81

Phosphorylated TAK1 dissociates from the TLR3 receptor complex

Phosphorylated TAK1 complexed with TRAF6-TAB1-TAB2/TAB3 leaves the activated TLR4 complex and translocates to the cytosol

Authored: Shamovsky, V, 2010-05-21Reviewed: Gillespie, ME, 2010-05-28Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2010-05-21

Reactome DB_ID: 177691

Reactome DB_ID: 168907

Reactome DB_ID: 847073

K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1 [cytosol]

K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1

Reactome DB_ID: 450152

Reactome DB_ID: 167923

EQUAL

504

EQUAL

Reactome DB_ID: 202527

O-phospho-L-threonine at 184

184

EQUAL

O-phospho-L-threonine at 187

187

EQUAL

606

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 446874

Reactome DB_ID: 2685681

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 124

124

EQUAL

522

EQUAL

Reactome Database ID Release 70847073Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=847073ReactomeR-HSA-847073

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-847073.4Reactome Database ID Release 70847070Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=847070ReactomeR-HSA-847070

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-847070.212242293Pubmed2002Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosolJiang, ZNinomiya-Tsuji, JQian, YMatsumoto, KLi, XMol Cell Biol 22:7158-67

Reactome Database ID Release 709014325Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014325ReactomeR-HSA-9014325

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014325.3GO0007249

GO biological process

TAK1 activates NFkB by phosphorylation and activation of IKKs complex

NF-kappaB is sequestered in the cytoplasm in a complex with inhibitor of NF-kappaB (IkB). Almost all NF-kappaB activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappaB from the complex. This allows translocation of NF-kappaB to the nucleus where it regulates gene expression.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Reviewed: Napetschnig, Johanna, 2012-11-16Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2011-08-12

IKBKA, IKBKB and IKBKG form IKK complex

The multimeric I kappa B kinase (IKK) complex is a key regulator of NFkB signaling, which is responsible for the phosphorylation of inhibitor kB (IkB). The phosphorylation by IKK triggers K48-linked ubiquitination of IkB leading proteasomal degradation of IkB, allowing translocation of NFkB factor to the nucleus, where it can activate transcription of a variety of genes participating in the immune and inflammatory response, cell adhesion, growth control, and protection against apoptosis (Alkalay I et al. 1995; Collins T et al. 1995; Kaltschmidt B et al. 2000; Oeckinghaus A and Ghosh S 2009). The IKK complex is composed of the two catalytic subunits, IKKA (IKBKA) and IKKB (IKBKB) kinases, and a regulatory subunit, NFkB essential modulator (IKBKG/NEMO/IKKG). IKBKG (NEMO) associates with the unphosphorylated IKK kinase C-termini and activates the IKK complex’s catalytic activity (Rothwarf DM et al. 1998). The molecular composition and stoichiometry of the IKK complex remains debatable, although the core IKK complex that range from 700 to 900 kDa is thought to consist of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies (DiDonato JA et al. 1997; May J et al. 2002; Tegethoff S et al. 2003; Marienfeld RB et al. 2006; Rushe M et al. 2008).

Authored: Shamovsky, Veronica, 2015-02-15Reviewed: D'Eustachio, Peter, 2014-09-06Reviewed: McDonald, Douglas R, 2015-02-15Edited: Shamovsky, Veronica, 2015-02-15

Reactome DB_ID: 168114

EQUAL

756

EQUAL

Reactome DB_ID: 168104

EQUAL

745

EQUAL

Reactome DB_ID: 168108

EQUAL

419

EQUAL

Reactome DB_ID: 168113

Reactome Database ID Release 705609665Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5609665ReactomeR-HSA-5609665

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5609665.118462684Pubmed2008Structure of a NEMO/IKK-associating domain reveals architecture of the interaction siteRushe, MiaSilvian, LauraBixler, SarahChen, Ling LingCheung, AnneBowes, ScottCuervo, HernanBerkowitz, StevenZheng, TimothyGuckian, KevinPellegrini, MariaLugovskoy, AlexeyStructure 16:798-8087479848Pubmed1995Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathwayAlkalay, IYaron, AHatzubai, AOrian, ACiechanover, ABen-Neriah, YProc Natl Acad Sci U S A 92:10599-60320066092Pubmed2009The NF-kappaB family of transcription factors and its regulationOeckinghaus, AndreaGhosh, SankarCold Spring Harb Perspect Biol 1:a00003417000764Pubmed2006Dimerization of the I kappa B kinase-binding domain of NEMO is required for tumor necrosis factor alpha-induced NF-kappa B activityMarienfeld, Ralf BPalkowitsch, LysannGhosh, SankarMol. Cell. Biol. 26:9209-199751060Pubmed1998IKK-gamma is an essential regulatory subunit of the IkappaB kinase complexRothwarf, D MZandi, ENatoli, GKarin, MNature 395:297-300

2.7.11.25

Activated TAK1 mediates phosphorylation of the IKK Complex

In humans, the IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta associated with a regulatory subunit, NEMO (IKKgamma). The activation of the IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO [Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Reviewed: Napetschnig, Johanna, 2012-11-16Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 168113

Reactome DB_ID: 113592

Reactome DB_ID: 177663

IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKB [cytosol]

IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKB

Activated IKK Complex

Reactome DB_ID: 202506

O-phospho-L-serine at 177

177

EQUAL

O-phospho-L-serine [MOD:00046]

O-phospho-L-serine at 181

181

EQUAL

756

EQUAL

Reactome DB_ID: 177667

O-phospho-L-serine at 176

176

EQUAL

O-phospho-L-serine at 180

180

EQUAL

745

EQUAL

Reactome DB_ID: 168108

EQUAL

419

EQUAL

Reactome Database ID Release 70177663Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177663ReactomeR-HSA-177663

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177663.3

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 772536

Activated TAK complexes [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

GO0004709

GO molecular function

Reactome Database ID Release 70177696Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177696Reactome Database ID Release 70168184Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168184ReactomeR-HSA-168184

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168184.49744859Pubmed1998Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and deathArch, RHGedrich, RWThompson, CBGenes Dev 12:2821-3011460167Pubmed2001TAK1 is a ubiquitin-dependent kinase of MKK and IKKWang, CDeng, LHong, MAkkaraju, GRInoue, JChen, ZJNature 412:346-5112221085Pubmed2002IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response programLi, XMassa, PEHanidu, APeet, GWAro, PSavitt, AMische, SLi, JMarcu, KBJ Biol Chem 277:45129-4019666475Pubmed2009The nemo binding domains of both IKKalpha and IKKbeta regulate IKK complex assembly and classical NFkappaB activationSolt, LAMadge, LAMay, MJJ Biol Chem

NFkB inhibitor binds NFkB complex

NFkB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called NFkB inhibitors (IkBs). IkBs proteins such as NFKBIA or NFKBIB are characterized by the presence of six to seven ankyrin repeat motifs, which mediate interaction with the Rel homology domain (RHD). RHD mediates DNA binding, dimerization and nuclear localization (Jacobs MD & Harrison SC 1998; Manavalan B et al. 2010). NFkB inhibitors (IkBs) mask the nuclear localization signal (NLS) of NFKB preventing its nuclear translocation (Jacobs MD & Harrison SC 1998; Cervantes CF et al. 2011). A key event in NFkB activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta)) by the IκB kinase (IKK) complex. The phosphorylated NFKBIA is recognized by the E3 ligase complex and targeted for ubiquitin-mediated proteasomal degradation, releasing the NFkB dimer p50/p65 into the nucleus to turn on target genes (Karin M & Ben-Neriah Y 2000, Kanarek N & Ben-Neriah Y 2012; Hoffmann A et al. 2006). Crystal structures of NFkB inhibitors:NFkB complexes revealed that an NFkB dimer binds to one IkB molecule (Jacobs MD & Harrison SC 1998; Ghosh G et 2012).

Authored: Shamovsky, Veronica, 2018-11-30Reviewed: D'Eustachio, Peter, 2018-12-04Edited: Shamovsky, Veronica, 2018-12-05

Reactome DB_ID: 168155

NFKB1(1-433), NFKB2(1-454):RELA [cytosol]

NFKB1(1-433), NFKB2(1-454):RELA

NFkB Complex

Converted from EntitySet in Reactome

Reactome DB_ID: 177656

NFKB1(1-433), NFKB2(1-454) [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNFKB2(1-454) [cytosol]NFKB1(1-433) [cytosol]

UniProtQ00653UniProtP19838

Reactome DB_ID: 168172

UniProt:Q04206 RELA

RELA

NFKB3RELAFUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The heterodimeric RELA-NFKB1 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. The NF-kappa-B heterodimeric RELA-NFKB1 and RELA-REL complexes, for instance, function as transcriptional activators. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The inhibitory effect of I-kappa-B on NF-kappa-B through retention in the cytoplasm is exerted primarily through the interaction with RELA. RELA shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Beside its activity as a direct transcriptional activator, it is also able to modulate promoters accessibility to transcription factors and thereby indirectly regulate gene expression. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells (PubMed:15790681). The NF-kappa-B homodimeric RELA-RELA complex appears to be involved in invasin-mediated activation of IL-8 expression.SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Homodimer; component of the NF-kappa-B p65-p65 complex. Component of the NF-kappa-B p65-p52 complex. May interact with ETHE1. Binds TLE5 and TLE1. Interacts with TP53BP2. Binds to and is phosphorylated by the activated form of either RPS6KA4 or RPS6KA5. Interacts with ING4 and this interaction may be indirect. Interacts with CARM1, USP48 and UNC5CL. Interacts with IRAK1BP1 (By similarity). Interacts with NFKBID (By similarity). Interacts with NFKBIA (PubMed:1493333). Interacts with GSK3B. Interacts with NFKBIB (By similarity). Interacts with NFKBIE. Interacts with NFKBIZ. Interacts with EHMT1 (via ANK repeats) (By similarity). Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with HDAC3; HDAC3 mediates the deacetylation of RELA. Interacts with HDAC1; the interaction requires non-phosphorylated RELA. Interacts with CBP; the interaction requires phosphorylated RELA. Interacts (phosphorylated at 'Thr-254') with PIN1; the interaction inhibits p65 binding to NFKBIA. Interacts with SOCS1. Interacts with UXT. Interacts with MTDH and PHF11. Interacts with ARRB2. Interacts with NFKBIA (when phosphorylated), the interaction is direct; phosphorylated NFKBIA is part of a SCF(BTRC)-like complex lacking CUL1. Interacts with RNF25. Interacts (via C-terminus) with DDX1. Interacts with UFL1 and COMMD1. Interacts with BRMS1; this promotes deacetylation of 'Lys-310'. Interacts with NOTCH2 (By similarity). Directly interacts with MEN1; this interaction represses NFKB-mediated transactivation. Interacts with AKIP1, which promotes the phosphorylation and nuclear retention of RELA. Interacts (via the RHD) with GFI1; the interaction, after bacterial lipopolysaccharide (LPS) stimulation, inhibits the transcriptional activity by interfering with the DNA-binding activity to target gene promoter DNA. Interacts (when acetylated at Lys-310) with BRD4; leading to activation of the NF-kappa-B pathway. Interacts with MEFV. Interacts with CLOCK (By similarity). Interacts (via N-terminus) with CPEN1; this interaction induces proteolytic cleavage of p65/RELA subunit and inhibition of NF-kappa-B transcriptional activity (PubMed:18212740). Interacts with FOXP3. Interacts with CDK5RAP3; stimulates the interaction of RELA with HDAC1, HDAC2 and HDAC3 thereby inhibiting NF-kappa-B transcriptional activity (PubMed:17785205). Interacts with DHX9; this interaction is direct and activates NF-kappa-B-mediated transcription (PubMed:15355351). Interacts with LRRC25 (PubMed:29044191). Interacts with TBX21 (By similarity). Interacts with KAT2A (By similarity). Interacts with ZBTB7A; involved in the control by RELA of the accessibility of target gene promoters (PubMed:29813070).SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein M2-1.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus MC132.SUBUNIT (Microbial infection) Interacts with herpes virus 8 virus protein LANA1.DOMAIN The transcriptional activation domain 3/TA3 does not participate to the direct transcriptional activity of RELA but is involved in the control by RELA of the accessibility of target gene promoters. Mediates interaction with ZBTB7A.DOMAIN The transcriptional activation domain 1/TA1 and the transcriptional activation domain 2/TA2 have direct transcriptional activation properties (By similarity). The 9aaTAD motif found within the transcriptional activation domain 2 is a conserved motif present in a large number of transcription factors that is required for their transcriptional transactivation activity (PubMed:17467953).PTM Ubiquitinated, leading to its proteasomal degradation. Degradation is required for termination of NF-kappa-B response.PTM Monomethylated at Lys-310 by SETD6. Monomethylation at Lys-310 is recognized by the ANK repeats of EHMT1 and promotes the formation of repressed chromatin at target genes, leading to down-regulation of NF-kappa-B transcription factor activity. Phosphorylation at Ser-311 disrupts the interaction with EHMT1 without preventing monomethylation at Lys-310 and relieves the repression of target genes (By similarity).PTM Phosphorylation at Ser-311 disrupts the interaction with EHMT1 and promotes transcription factor activity (By similarity). Phosphorylation on Ser-536 stimulates acetylation on Lys-310 and interaction with CBP; the phosphorylated and acetylated forms show enhanced transcriptional activity. Phosphorylation at Ser-276 by RPS6KA4 and RPS6KA5 promotes its transactivation and transcriptional activities.PTM Reversibly acetylated; the acetylation seems to be mediated by CBP, the deacetylation by HDAC3 and SIRT2. Acetylation at Lys-122 enhances DNA binding and impairs association with NFKBIA. Acetylation at Lys-310 is required for full transcriptional activity in the absence of effects on DNA binding and NFKBIA association. Acetylation at Lys-310 promotes interaction with BRD4. Acetylation can also lower DNA-binding and results in nuclear export. Interaction with BRMS1 promotes deacetylation of Lys-310. Lys-310 is deacetylated by SIRT2.PTM S-nitrosylation of Cys-38 inactivates the enzyme activity.PTM Sulfhydration at Cys-38 mediates the anti-apoptotic activity by promoting the interaction with RPS3 and activating the transcription factor activity.PTM Sumoylation by PIAS3 negatively regulates DNA-bound activated NF-kappa-B.PTM Proteolytically cleaved within a conserved N-terminus region required for base-specific contact with DNA in a CPEN1-mediated manner, and hence inhibits NF-kappa-B transcriptional activity (PubMed:18212740).DISEASE A chromosomal aberration involving C11orf95 is found in more than two-thirds of supratentorial ependymomas. Translocation with C11orf95 produces a C11orf95-RELA fusion protein. C11orf95-RELA translocations are potent oncogenes that probably transform neural stem cells by driving an aberrant NF-kappa-B transcription program (PubMed:24553141).

UniProtQ04206

EQUAL

551

EQUAL

Reactome Database ID Release 70168155Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168155ReactomeR-HSA-168155

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168155.3Converted from EntitySet in Reactome

Reactome DB_ID: 168143

NFkB inhibitor [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNFKBIB [cytosol]NFKBIA [cytosol]

UniProtQ15653UniProtP25963

Reactome DB_ID: 168130

NFkB inhibitor:NFkB complex [cytosol]

NFkB inhibitor:NFkB complex

IkBs:NFkB

Reactome DB_ID: 168155

Converted from EntitySet in Reactome

Reactome DB_ID: 168143

Reactome Database ID Release 70168130Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168130ReactomeR-HSA-168130

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168130.2Reactome Database ID Release 709630923Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9630923ReactomeR-HSA-9630923

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630923.121203422Pubmed2010Structure-function relationship of cytoplasmic and nuclear IκB proteins: an in silico analysisManavalan, BalachandranBasith, ShaherinChoi, Yong-MinLee, GwangChoi, SangdunPLoS ONE 5:e1578222435548Pubmed2012Regulation of NF-κB by ubiquitination and degradation of the IκBsKanarek, NaamaBen-Neriah, YinonImmunol. Rev. 246:77-9410837071Pubmed2000Phosphorylation meets ubiquitination: the control of NF-[kappa]B activityKarin, MBen-Neriah, YAnnu. Rev. Immunol. 18:621-639865693Pubmed1998Structure of an IkappaBalpha/NF-kappaB complexJacobs, M DHarrison, S CCell 95:749-5817072323Pubmed2006Transcriptional regulation via the NF-kappaB signaling moduleHoffmann, ANatoli, GGhosh, GOncogene 25:6706-1621094161Pubmed2011The RelA nuclear localization signal folds upon binding to IκBαCervantes, Carla FBergqvist, SimonKjaergaard, MagnusKroon, GerardSue, Shih-CheDyson, H JaneKomives, Elizabeth AJ. Mol. Biol. 405:754-6415145317Pubmed2004The two NF-kappaB activation pathways and their role in innate and adaptive immunityBonizzi, GKarin, MTrends Immunol 25:280-822435546Pubmed2012NF-κB regulation: lessons from structuresGhosh, GourisankarWang, Vivien Ya-FanHuang, De-BinFusco, AmandaImmunol. Rev. 246:36-58

2.7.11

Phospho-IKK Complex phosphorylates NFkB inhibitor within the NFkB inhibitor:NFkB complex

In human, IkB is an inhibitory protein that sequesters NF-kB in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end in each of the NF-kB subunits. A key event in NF-kB activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human IkB-alpha or Ser19 and Ser22 of human IkB-beta); Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kB.

Reviewed: D'Eustachio, P, 2011-12-07Reviewed: Upton, JW, Mocarski, ES, 2012-02-19Reviewed: Napetschnig, Johanna, 2012-11-16Reviewed: Fitzgerald, Katherine A, 2012-11-13Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 113592

Reactome DB_ID: 168130

Converted from EntitySet in Reactome

Reactome DB_ID: 177678

Phospho-NF-kappaB Inhibitor [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S32,S36-NFKBIA [cytosol]p-S19,S23-NFKBIB [cytosol]

Reactome DB_ID: 168155

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 177663

Reactome Database ID Release 70450351Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450351Reactome Database ID Release 70168140Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168140ReactomeR-HSA-168140

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168140.427701768Pubmed2017Double phosphorylation-induced structural changes in the signal-receiving domain of IκBα in complex with NF-κBYazdi, SamiraNaumann, MichaelStein, MatthiasProteins 85:17-2910723127Pubmed2000Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complexGil, JAlcami, JEsteban, MOncogene 19:1369-78

INHIBITION

Reactome Database ID Release 708952695Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8952695ReactomeR-HSA-8952695

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8952695.112672800Pubmed2003KappaB-Ras binds to the unique insert within the ankyrin repeat domain of IkappaBbeta and regulates cytoplasmic retention of IkappaBbeta x NF-kappaB complexesChen, YiWu, JoannGhosh, GourisankarJ. Biol. Chem. 278:23101-6Converted from EntitySet in Reactome

Reactome DB_ID: 8952687

NKIRAS [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNKIRAS2 [cytosol]NKIRAS1 [cytosol]

UniProtQ9NYR9UniProtQ9NYS0

NFkB complex is transported from cytosol to nucleus

NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NFkappa-B2), All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefor, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes.

Authored: Shamovsky, V, 2009-12-16Reviewed: D'Eustachio, P, 2011-12-07Reviewed: Upton, JW, Mocarski, ES, 2012-02-19Reviewed: Napetschnig, Johanna, 2012-11-16Reviewed: Fitzgerald, Katherine A, 2012-11-13Reviewed: Jin, Lei, 2013-05-21Reviewed: Wu, Jiaxi, 2013-05-21Edited: Shamovsky, V, 2013-05-17

Reactome DB_ID: 168155

Reactome DB_ID: 177673

NFkB Complex [nucleoplasm]

NFkB Complex

Reactome DB_ID: 177676

EQUAL

551

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 177662

Nuclear factor NF-kappa-B [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNFKB2(1-454) [nucleoplasm]NFKB1(1-433) [nucleoplasm]

Reactome Database ID Release 70177673Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177673ReactomeR-HSA-177673

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177673.1Reactome Database ID Release 70168166Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168166ReactomeR-HSA-168166

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168166.416056267Pubmed2005Ubiquitin signalling in the NF-kappaB pathwayChen, ZJNat Cell Biol 7:758-65

ACTIVATION

Though the signaling cascade is unclear, several pieces of experimental data suggest that activation of AGER leads to sustained activation and upregulation of NFkappaB, measured as NFkappaB translocation to the nucleus, and increased levels of de novo synthesized NFkappaB.

Reactome Database ID Release 70879381Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879381ReactomeR-HSA-879381

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-879381.211723063Pubmed2001Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaBBierhaus, ASchiekofer, SSchwaninger, MAndrassy, MHumpert, PMChen, JHong, MLuther, THenle, TKlöting, IMorcos, MHofmann, MTritschler, HWeigle, BKasper, MSmith, MPerry, GeorgeSchmidt, AMStern, DMHäring, Hans-UlrichSchleicher, ENawroth, PPDiabetes 50:2792-808

Reactome DB_ID: 879365

plasma membraneGO0005886AGER ligands:AGER [plasma membrane]

AGER ligands:AGER

Reactome DB_ID: 197639

UniProt:Q15109 AGER

AGER

RAGEAGERFUNCTION Mediates interactions of advanced glycosylation end products (AGE). These are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. Acts as a mediator of both acute and chronic vascular inflammation in conditions such as atherosclerosis and in particular as a complication of diabetes. AGE/RAGE signaling plays an important role in regulating the production/expression of TNF-alpha, oxidative stress, and endothelial dysfunction in type 2 diabetes. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Receptor for amyloid beta peptide. Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. Can also bind oligonucleotides.SUBUNIT Interacts with S100A1 and APP (By similarity). Interacts with S100B, S100A12 and S100A14. Constitutive homodimer; disulfide-linked.TISSUE SPECIFICITY Endothelial cells.

UniProtQ15109

EQUAL

404

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 879455

extracellular regionGO0005576

AGER ligands [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySAA1(19-122) [extracellular region]HMGB1 [extracellular region]APP(672-713) [extracellular region]APP(672-711) [extracellular region]

UniProtP0DJI8UniProtP09429UniProtP05067Reactome Database ID Release 70879365Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879365ReactomeR-HSA-879365

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-879365.1

Reactome Database ID Release 70445989Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=445989ReactomeR-HSA-445989

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-445989.315837794Pubmed2005Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genesThiefes, AWolter, SMushinski, JFHoffmann, EDittrich-Breiholz, OGraue, NDörrie, ASchneider, HWirth, DLuckow, BResch, KKracht, MJ Biol Chem 280:27728-41GO0051092

GO biological process

MAP kinase activation

The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002). There are three major groups of MAP kinases<ul><li>the extracellular signal-regulated protein kinases ERK1/2, <li>the p38 MAP kinase<li> and the c-Jun NH-terminal kinases JNK.</ul>ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1

C-Jun NH2 terminal kinases (JNKs) are an evolutionarily conserved family of serine/threonine protein kinases, that belong to mitogen activated protein kinase family (MAPKs - also known as stress-activated protein kinases, SAPKs). The JNK pathway is activated by heat shock, or inflammatory cytokines, or UV radiation. The JNKs are encoded by at least three genes: JNK1/SAPK-gamma, JNK2/SAPK-alpha and JNK3/ SAPK-beta. The first two are ubiquitously expressed, whereas the JNK3 protein is found mainly in brain and to a lesser extent in heart and testes. As a result of alternative gene splicing all cells express distinct active forms of JNK from 46 to 55 kDa in size. Sequence alignment of these different products shows homologies of >80%. In spite of this similarity, the multiple JNK isoforms differ in their ability to bind and phosphorylate different target proteins, thus leading to the distinctive cellular processes: induction of apoptosis, or enhancment of cell survival, or proliferation.Activation of JNKs is mediated by activated TAK1 which phosphorylates two dual specificity enzymes MKK4 (MAPK kinase 4) and MKK7(MAPK kinase 7).

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

2.7.11.25

Activated TAK1 phosphorylates MKK4/MKK7

In human, phosphorylation of MKK4 (MAP2K4) and MKK7 (MAP2K7) by TAK1 occurs at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7 and Ser257, Thr261 in MKK4.Cell lines lacking MKK4 exhibit defective activation of JNK and AP-1 dependent transcription activity in response to some cellular stresses; JNK and p38 MAPK activities were decreased by around 80% and 20%, respectively, following deletion of the mkk4 gene.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Converted from EntitySet in Reactome

Reactome DB_ID: 450305

MAP2K7,MAP2K4 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAP2K4 [cytosol]MAP2K7 [cytosol]

UniProtP45985UniProtO14733

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 450299

p-MAP2K4/p-MAP2K7 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S257,T261-MAP2K4 [cytosol]p-S271,T275-MAP2K7 [cytosol]

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 772536

Reactome Database ID Release 70450337Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450337ReactomeR-HSA-450337

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450337.18533096Pubmed1995Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transductionYamaguchi, KShirakabe, KShibuya, HIrie, KOishi, IUeno, NTaniguchi, TNishida, EMatsumoto, KScience 270:2008-1117875933Pubmed2007Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature deathWang, XNadarajah, BRobinson, ACMcColl, BWJin, JWDajas-Bailador, FBoot-Handford, RPTournier, CMol Cell Biol 27:7935-46

2.7.11

Phosphorylation of human JNKs by activated MKK4/MKK7

Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 cascade requires both MKK4 and MKK7. Some studies reported that in three JNK isoforms tested MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183).

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gay, NJ, 2006-04-24 16:48:17Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 450289

MAPK8,9,10 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAPK8 [cytosol]MAPK9 [cytosol]MAPK10 [cytosol]

UniProtP45983UniProtP45984UniProtP53779Converted from EntitySet in Reactome

Reactome DB_ID: 450226

p-MAPK8,9,10 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T,Y-MAPK8 [cytosol]p-T221,Y223-MAPK10 [cytosol]p-T183,Y185-MAPK9 [cytosol]

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 450299

GO0008545

GO molecular function

Reactome Database ID Release 70450334Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450334Reactome Database ID Release 70168162Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168162ReactomeR-HSA-168162

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168162.211062067Pubmed2000Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7Fleming, YArmstrong, CGMorrice, NPaterson, AGoedert, MCohen, PBiochem J 352:145-549162092Pubmed1997Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo.Deacon, KBlank, JLJ Biol Chem 272:14489-9613130464Pubmed2003Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNKSundarrajan, MBoyle, DLChabaud-Riou, MHammaker, DFirestein, GSArthritis Rheum 48:2450-6018713996Pubmed2008Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinasesYoshizawa, THammaker, DSweeney, SEBoyle, DLFirestein, GSJ Immunol 181:3252-8

Activated human JNKs migrate to nucleoplasm

c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus, where they associate and activate their target transcription factors.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Converted from EntitySet in Reactome

Reactome DB_ID: 450226

Converted from EntitySet in Reactome

Reactome DB_ID: 450253

p-MAPK8,9,10 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T,Y-MAPK8 [nucleoplasm]p-T221,Y223-MAPK10 [nucleoplasm]p-T183,Y185-MAPK9 [nucleoplasm]

Reactome Database ID Release 70450348Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450348ReactomeR-HSA-450348

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450348.112193592Pubmed2002Evidence of functional modulation of the MEKK/JNK/cJun signaling cascade by the low density lipoprotein receptor-related protein (LRP)Lutz, CNimpf, JJenny, MBoecklinger, KEnzinger, CUtermann, GBaier-Bitterlich, GBaier, GJ Biol Chem 277:43143-519195981Pubmed1997A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion.Mizukami, YYoshioka, KMorimoto, SYoshida, KJ Biol Chem 272:16657-62

Reactome Database ID Release 70450321Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450321ReactomeR-HSA-450321

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450321.216937364Pubmed2006The isoform-specific functions of the c-Jun N-terminal Kinases (JNKs): differences revealed by gene targetingBogoyevitch, MABioessays 28:923-349851932Pubmed1998Defective T cell differentiation in the absence of Jnk1Dong, CYang, DDWysk, MWhitmarsh, AJDavis, RJFlavell, RAScience 282:2092-526988982Pubmed2016IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cellsLi, Jing-kunNie, LinZhao, Yun-pengZhang, Yuan-qiangWang, XiaoqingWang, Shuai-shuaiLiu, YiZhao, HuaCheng, LeiJ Transl Med 14:778177321Pubmed1994The stress-activated protein kinase subfamily of c-Jun kinasesKyriakis, JMBanerjee, PNikolakaki, EDai, TRubie, EAAhmad, MFAvruch, JosephWoodgett, JRNature 369:156-60GO0007254

GO biological process

activated TAK1 mediates p38 MAPK activation

p38 mitogen-activated protein kinase (MAPK) belongs to a highly conserved family of serine/threonine protein kinases. The p38 MAPK-dependent signaling cascade is activated by pro-inflammatory or stressful stimuli such as ultraviolet radiation, oxidative injury, heat shock, cytokines, and other pro-inflammatory stimuli. p38 MAPK exists as four isoforms (alpha, beta, gamma, and delta). Of these, p38alpha and p38beta are ubiquitously expressed while p38gamma and p38delta are differentially expressed depending on tissue type. Each isoform is activated by upstream kinases including MAP kinase kinases (MKK) 3, 4, and 6, which in turn are phosphorylated by activated TAK1 at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.Once p38 MAPK is phosphorylated it activates numerous downstream substrates, including MAPK-activated protein kinase-2 and 3 (MAPKAPK-2 or 3) and mitogen and stress-activated kinase-1/2 (MSK1/2). MAPKAPK-2/3 and MSK1/2 function to phosphorylate heat shock protein 27 (HSP27) and cAMP-response element binding protein transcriptional factor, respectively. Other transcription factors, including activating transcription factor 2, Elk, CHOP/GADD153, and myocyte enhancer factor 2, are known to be regulated by these kinases.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

2.7.11.25

activated human TAK1 phosphorylates MKK3/MKK6

Human MKK3 (MAP2K4) and MKK6 (MAP2K6) are two closely related dual-specificity protein kinases. Both are activated by cellular stress and inflammatory cytokines, and both phosphorylate and activate p38 MAP kinase at its activation site Thr-Gly-Tyr but do not phosphorylate or activate Erk1/2 or SAPK/JNK. Activation of MKK3 and MKK6 occurs through phosphorylation of serine and threonine residues at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loop. Residues involved into these protein kinases activation correspond to human sites Ser189 and Thr193 for MKK3 and Ser207 and Thr211 for MKK6 .

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2011-08-12

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 167916

MAP2K3,MAP2K6 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAP2K6 [cytosol]MAP2K3 [cytosol]

UniProtP52564UniProtP46734Converted from EntitySet in Reactome

Reactome DB_ID: 167984

p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S207,T211-MAP2K6 [cytosol]p-S189,T193-MAP2K3 [cytosol]

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 772536

Reactome Database ID Release 70450346Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450346ReactomeR-HSA-450346

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450346.18622669Pubmed1996MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathwayRaingeaud, JWhitmarsh, AJBarrett, TDerijard, BDavis, RJMol Cell Biol 16:1247-55

Phosphorylated MKK3/MKK6 migrates to nucleus

The p38 activators MKK3 (MAP2K3) and MKK6 (MAP2K6) were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Converted from EntitySet in Reactome

Reactome DB_ID: 167984

Converted from EntitySet in Reactome

Reactome DB_ID: 450343

p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S189,T193-MAP2K3 [nucleoplasm]p-S207,T211-MAP2K6 [nucleoplasm]

Reactome Database ID Release 70450296Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450296ReactomeR-HSA-450296

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450296.29768359Pubmed1998Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2Ben-Levy, RHooper, SWilson, RPaterson, HFMarshall, CJCurr Biol 8:1049-577535770Pubmed1995Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonineRaingeaud, JGupta, SRogers, JSDickens, MHan, JUlevitch, RJDavis, RJJ Biol Chem 270:7420-6

2.7.11

Activated human MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3

The MAPK level components of this cascade are p38MAPK-alpha, -beta, -gamma and -sigma. All of those isoforms are activated by phosphorylation of the Thr and Tyr in the Thr-Gly-Tyr motif in their activation loops.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Reactome DB_ID: 29358

Reactome DB_ID: 450269

p38 MAPK:MAPKAPK2,3 [nucleoplasm]

p38 MAPK:MAPKAPK2,3

Converted from EntitySet in Reactome

Reactome DB_ID: 450217

MAPKAP2,3 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAPKAPK3 [nucleoplasm]MAPKAPK2 [nucleoplasm]

UniProtQ16644UniProtP49137Converted from EntitySet in Reactome

Reactome DB_ID: 203795

MAP kinase p38 alpha/beta [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAPK11 [nucleoplasm]MAPK14 [nucleoplasm]

UniProtQ15759UniProtQ16539Reactome Database ID Release 70450269Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450269ReactomeR-HSA-450269

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450269.2

Reactome DB_ID: 450213

p-p38 MAPK: MAPKAPK2,3 [nucleoplasm]

p-p38 MAPK: MAPKAPK2,3

Converted from EntitySet in Reactome

Reactome DB_ID: 450217

Converted from EntitySet in Reactome

Reactome DB_ID: 198703

p-p38 MAPK alpha/beta [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T180,Y182-MAPK14 [nucleoplasm]p-T180,Y182-MAPK11 [nucleoplasm]

Reactome Database ID Release 70450213Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450213ReactomeR-HSA-450213

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450213.2

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 450343

GO0004708

GO molecular function

Reactome Database ID Release 70450239Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450239Reactome Database ID Release 70450333Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450333ReactomeR-HSA-450333

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450333.1

2.7.11

Active p38 MAPK phosphorylates MAPKAPK2 or 3

Human p38 MAPK alpha forms a complex with MK2 even when the signaling pathway is not activated. This heterodimer is found mainly in the nucleus. The crystal structure of the unphosphorylated p38alpha-MK2 heterodimer was determined. The C-terminal regulatory domain of MK2 binds in the docking groove of p38 MAPK alpha, and the ATP-binding sites of both kinases are at the heterodimer interface (ter Haar et al. 2007).Upon activation, p38 MAPK alpha activates MK2 by phosphorylating Thr-222, Ser-272, and Thr-334 (Ben-Levy et al. 1995). The phosphorylation of MK2 at Thr-334 attenuates the affinity of the binary complex MK2:p38 alpha by an order of magnitude and leads to a large conformational change of an autoinhibitory domain in MK2. This conformational change unmasks not only the MK2 substrate-binding site but also the MK2 nuclear export signal (NES) thus leading to the MK2:p38 alpha translocation from the nucleus to the cytoplasm. Cytoplasmic active MK2 then phosphorylates downstream targets such as the heat-shock protein HSP27 and tristetraprolin (TTP) (Meng et al. 2002, Lukas et al. 2004, White et al. 2007).MAPKAPK (MAPK-activated protein) kinase 3 (MK3, also known as 3pK) has been identified as the second p38 MAPK-activated kinase that is stimulated by different stresses (McLaughlin et al. 1996; Sithanandam et al. 1996; reviewed in Gaestel 2006). MK3 shows 75% sequence identity to MK2 and, like MK2, is activated by p38 MAPK alpha and p38 MAPK beta. MK3 phosphorylates peptide substrates with kinetic constants similar to MK2 and phosphorylates the same serine residues in HSP27 at the same relative rates as MK2 (Clifton et al. 1996) indicating an identical phosphorylation-site consensus sequence. Hence, it is assumed that its substrate spectrum is either identical to or at least overlapping with MK2.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Reactome DB_ID: 450213

Reactome DB_ID: 29358

Reactome DB_ID: 113582

Reactome DB_ID: 450254

p-p38 MAPK:p-MAPKAPK2/3 [nucleoplasm]

p-p38 MAPK:p-MAPKAPK2/3

Converted from EntitySet in Reactome

Reactome DB_ID: 450261

Active MAPKAP kinase [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S,2T-MAPKAPK3 [nucleoplasm]p-T222,S272,T334-MAPKAPK2 [nucleoplasm]

Converted from EntitySet in Reactome

Reactome DB_ID: 198703

Reactome Database ID Release 70450254Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450254ReactomeR-HSA-450254

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450254.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 450213

Reactome Database ID Release 70450303Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450303Reactome Database ID Release 70450222Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450222ReactomeR-HSA-450222

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450222.117395714Pubmed2007Molecular basis of MAPK-activated protein kinase 2:p38 assemblyWhite, APargellis, CAStudts, JMWerneburg, BGFarmer BT, 2ndProc Natl Acad Sci U S A 104:6353-88774846Pubmed1996A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stressClifton, A DYoung, P RCohen, PFEBS Lett. 392:209-1412171911Pubmed2002Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear exportMeng, WSwenson, LLFitzgibbon, MJHayakawa, KTer Haar, EBehrens, AEFulghum, JRLippke, JAJ Biol Chem 277:37401-515287722Pubmed2004Catalysis and function of the p38 alpha.MK2a signaling complexLukas, SMKroe, RRWildeson, JPeet, GWFrego, LDavidson, WIngraham, RHPargellis, CALabadia, MEWerneburg, BGBiochemistry 43:9950-608626550Pubmed1996Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinaseMcLaughlin, M MKumar, SMcDonnell, P CVan Horn, SLee, J CLivi, G PYoung, P RJ. Biol. Chem. 271:8488-928622688Pubmed19963pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene regionSithanandam, GLatif, FDuh, F MBernal, RSmola, ULi, HKuzmin, IWixler, VGeil, LShrestha, SMol. Cell. Biol. 16:868-768846784Pubmed1995Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2Ben-Levy, RLeighton, IADoza, YNAttwood, PMorrice, NMarshall, CJCohen, PEMBO J 14:5920-3017255097Pubmed2007Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimerTer Haar, EPrabhakar, PLiu, XLepre, CJ Biol Chem 282:9733-9

Nuclear export of human p38 MAPK mediated by its substrate MAPKAPK2 or 3

p38 MAPK alpha does not have a nuclear export signal (NES) and cannot leave the nucleus by itself, but rather needs to be associated with MAP kinase-activated protein kinase 2 (MAPKAPK2 or MK2). The NES of MAPKAPK2 facilitates the transport of both kinases from the nucleus to the cytoplasm but only after MK2 has been phosphorylated by p38alpha.p38 MAPK alpha phosphorylates MK2 at Thr222, Ser272, and Thr334. The phosphorylation of Thr334 but not the kinase activity of MK2 has been demonstrated to be critical for the nuclear export of the p38 alpha - MK2 complex. Phosphorylation of Thr334 is believed to induce a conformational change in the complex exposing NES prior to interaction with the leptomycin B-sensitive nuclear export receptor.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Reactome DB_ID: 450254

Reactome DB_ID: 450241

p-p38 MAPK: p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3 [cytosol]

p-p38 MAPK: p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3

Converted from EntitySet in Reactome

Reactome DB_ID: 170997

p-p38 MAPK alpha/beta [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T180,Y182-MAPK11 [cytosol]p-T180,Y182-MAPK14 [cytosol]

Converted from EntitySet in Reactome

Reactome DB_ID: 187726

p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S,2T-MAPKAPK3 [cytosol]p-S272,T222,T334-MAPKAPK2 [cytosol]

Reactome Database ID Release 70450241Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450241ReactomeR-HSA-450241

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450241.2Reactome Database ID Release 70450257Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450257ReactomeR-HSA-450257

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450257.1

Reactome Database ID Release 70450302Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450302ReactomeR-HSA-450302

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450302.210878576Pubmed2000p38 MAPK signalling cascades: ancient roles and new functionsMartin-Blanco, EBioessays 22:637-45GO0000187

GO biological process

MAP3K8 (TPL2)-dependent MAPK1/3 activation

Tumor progression locus-2 (TPL2, also known as COT and MAP3K8) functions as a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) in various stress-responsive signaling cascades. MAP3K8 (TPL2) mediates phosphorylation of MAP2Ks (MEK1/2) which in turn phosphorylate MAPK (ERK1/2) (Gantke T et al., 2011).In the absence of extra-cellular signals, cytosolic MAP3K8 (TPL2) is held inactive in the complex with ABIN2 (TNIP2) and NFkB p105 (NFKB1) (Beinke S et al., 2003; Waterfield MR et al., 2003; Lang V et al., 2004). This interaction stabilizes MAP3K8 (TPL2) but also prevents MAP3K8 and NFkB from activating their downstream signaling cascades by inhibiting the kinase activity of MAP3K8 and the proteolysis of NFkB precursor protein p105. Upon activation of MAP3K8 by various stimuli (such as LPS, TNF-alpha, and IL-1 beta), IKBKB phosphorylates NFkB p105 (NFKB1) at Ser927 and Ser932, which trigger p105 proteasomal degradation and releases MAP3K8 from the complex (Beinke S et al., 2003, 2004; Roget K et al., 2012). Simultaneously, MAP3K8 is activated by auto- and/or transphosphorylation (Gantke T et al. 2011; Yang HT et al. 2012). The released active MAP3K8 phosphorylates its substrates, MAP2Ks. The free MAP3K8, however, is also unstable and is targeted for proteasome-mediated degradation, thus restricting prolonged activation of MAP3K8 (TPL2) and its downstream signaling pathways (Waterfield MR et al. 2003; Cho J et al., 2005). Furthermore, partially degraded NFkB p105 (NFKB1) into p50 can dimerize with other NFkB family members to regulate the transcription of target genes.MAP3K8 activity is thought to regulate the dynamics of transcription factors that control an expression of diverse genes involved in growth, differentiation, and inflammation. Suppressing the MAP3K8 kinase activity with selective inhibitors, such as C8-chloronaphthyridine-3-carbonitrile, caused a significant reduction in TNFalpha production in LPS- and IL-1beta-induced both primary human monocytes and human blood (Hall JP et al. 2007). Similar results have been reported for mouse LPS-stimulated RAW264.7 cells (Hirata K et al. 2010). Moreover, LPS-stimulated macrophages derived from Map3k8 knockout mice secreted lower levels of pro-inflammatory cytokines such as TNFalpha, Cox2, Pge2 and CXCL1 (Dumitru CD et al. 2000; Eliopoulos AG et al. 2002). Additionally, bone marrow-derived dendritic cells (BMDCs) and macrophages from Map3k8 knockout mice showed significantly lower expression of IL-1beta in response to LPS, poly IC and LPS/MDP (Mielke et al., 2009). However, several other studies seem to contradict these findings and Map3k8 deficiency in mice has been also reported to enhance pro-inflammatory profiles. Map3k8 deficiency in LPS-stimulated macrophages was associated with an increase in nitric oxide synthase 2 (NOS2) expression (López-Peláez et al., 2011). Similarly, expression of IRAK-M, whose function is to compete with IL-1R-associated kinase (IRAK) family of kinases, was decreased in Map3k8-/- macrophages while levels of TNF and IL6 were elevated (Zacharioudaki et al., 2009). Moreover, significantly higher inflammation level was observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated Map3k8-/- mouse skin compared to WT skin (DeCicco-Skinner K. et al., 2011). Additionally, MAP3K8 activity is associated with NFkB inflammatory pathway. High levels of active p65 NFkB were observed in the nucleus of Map3k8 -/- mouse keratinocytes that dramatically increased within 15-30 minutes of TPA treatment. Similarly, increased p65 NFkB was observed in Map3k8-deficient BMDC both basally and after stimulation with LPS when compared to wild type controls (Mielke et al., 2009). The data opposes the findings that Map3k8-deficient mouse embryo fibroblasts and human Jurkat T cells with kinase domain-deficient protein have a reduction in NFkB activation but only when certain stimuli are administered (Lin et al., 1999; Das S et al., 2005). Thus, it is possible that whether MAP3K8 serves more of a pro-inflammatory or anti-inflammatory role may depend on cell- or tissue type and on stimuli (LPS vs. TPA, etc.) (Mielke et al., 2009; DeCicco-Skinner K. et al., 2012).MAP3K8 has been also studied in the context of carcinogenesis, however the physiological role of MAP3K8 in the etiology of human cancers is also convoluted (Vougioukalaki M et al., 2011; DeCicco-Skinner K. et al., 2012).

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

NFKB p105, TPL2 (COT) and ABIN2 form a stable complex

The C-terminal half of NFKB1 p105 forms a high-affinity stoichiometric association with MAP3K8 (TPL2) via two distinct interactions (Belich et al. 1999; Beinke et al. 2003). The Tpl2 C-terminus (residues 398-467) binds to a region N-terminal to the p105 ankyrin repeat region (human p105 residues 497-534), whereas the Tpl2 kinase domain interacts with the p105 death domain (Beinke et al. 2003). In unstimulated macrophages, all detectable Tpl2 is associated with p105 (Belich et al. 1999; Lang et al. 2004). Binding to p105 maintains the stability of Tpl2 but inhibits Tpl2 MEK kinase activity by preventing access to MEK (Beinke et al. 2003; Waterfield et al. 2003). Tpl2 phosphorylation at Thr-290 may also play a role in the activation of Tpl2 (Cho & Tsichlis 2005). A20-binding inhibitor of NFkappaB2 (ABIN-2 ot TNIP2) interacts with Tpl2 and p105 but preferentially forms a ternary complex with both proteins. As ABIN2 is a polyubiquitin binding protein, it has been suggested that it may facilitate recruitment of the p105/Tpl2 complex to the activated IKK complex, allowing IKK2 induced p105 phosphorylation and consequent Tpl2 activation.

Authored: Ray, KP, 2010-05-17Reviewed: Pinteaux, E, 2010-05-17Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Jupe, S, 2010-05-17

Reactome DB_ID: 451607

UniProt:P19838 NFKB1

NFKB1

NFKB1FUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105.SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-p50 complex. Homodimer; component of the NF-kappa-B p50-p50 complex. Component of the NF-kappa-B p105-p50 complex. Component of the NF-kappa-B p50-c-Rel complex. Component of a complex consisting of the NF-kappa-B p50-p50 homodimer and BCL3. Also interacts with MAP3K8. NF-kappa-B p50 subunit interacts with NCOA3 coactivator, which may coactivate NF-kappa-B dependent expression via its histone acetyltransferase activity. Interacts with DSIPI; this interaction prevents nuclear translocation and DNA-binding. Interacts with SPAG9 and UNC5CL. NFKB1/p105 interacts with CFLAR; the interaction inhibits p105 processing into p50. NFKB1/p105 forms a ternary complex with MAP3K8 and TNIP2. Interacts with GSK3B; the interaction prevents processing of p105 to p50. NFKB1/p50 interacts with NFKBIE. NFKB1/p50 interacts with NFKBIZ. Nuclear factor NF-kappa-B p50 subunit interacts with NFKBID (By similarity). Directly interacts with MEN1. Interacts with HIF1AN.INDUCTION By phorbol ester and TNF.DOMAIN The C-terminus of p105 might be involved in cytoplasmic retention, inhibition of DNA-binding, and transcription activation.DOMAIN Glycine-rich region (GRR) appears to be a critical element in the generation of p50.PTM While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p50 making it an acceptable substrate for the proteasome. This process is known as cotranslational processing. The processed form is active and the unprocessed form acts as an inhibitor (I kappa B-like), being able to form cytosolic complexes with NF-kappa B, trapping it in the cytoplasm. Complete folding of the region downstream of the GRR repeat precludes processing.PTM Phosphorylation at 'Ser-903' and 'Ser-907' primes p105 for proteolytic processing in response to TNF-alpha stimulation. Phosphorylation at 'Ser-927' and 'Ser-932' are required for BTRC/BTRCP-mediated proteolysis.PTM Polyubiquitination seems to allow p105 processing.PTM S-nitrosylation of Cys-61 affects DNA binding.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation.

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Reactome DB_ID: 451661

UniProt:Q8NFZ5 TNIP2

TNIP2

TNIP2FLIP1ABIN2FUNCTION Inhibits NF-kappa-B activation by blocking the interaction of RIPK1 with its downstream effector NEMO/IKBKG. Forms a ternary complex with NFKB1 and MAP3K8 but appears to function upstream of MAP3K8 in the TLR4 signaling pathway that regulates MAP3K8 activation. Involved in activation of the MEK/ERK signaling pathway during innate immune response; this function seems to be stimulus- and cell type specific. Required for stability of MAP3K8. Involved in regulation of apoptosis in endothelial cells; promotes TEK agonist-stimulated endothelial survival. May act as transcriptional coactivator when translocated to the nucleus. Enhances CHUK-mediated NF-kappa-B activation involving NF-kappa-B p50-p65 and p50-c-Rel complexes.SUBUNIT Interacts with STK11/LKB1, TNFAIP3, IKBKG, NFKB1, MAP3K8, TEK, RIPK1, CHUK, IKBKB and SMARCD1. Interacts with polyubiquitin.TISSUE SPECIFICITY Ubiquitously expressed in all tissues examined.PTM In vitro phosphorylated by CHUK.PTM Ubiquitinated; undergoes 'Lys-48'-linked polyubiquitination probably leading to constitutive proteasomal degradation which can be impaired by IKK-A/CHUK or IKBKB probably involving deubiquitination.

UniProtQ8NFZ5

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429

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Reactome DB_ID: 389388

UniProt:P41279 MAP3K8

MAP3K8

ESTFCOTMAP3K8FUNCTION Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.SUBUNIT Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts with NFKB1; the interaction increases the stability of MAP3K8 but inhibits its MEK phosphorylation activity, whereas loss of interaction following LPS stimulation leads to its degradation. Interacts with CD40 and TRAF6; the interaction is required for ERK activation. Interacts with KSR2; the interaction inhibits ERK and NF-kappa-B activation.TISSUE SPECIFICITY Expressed in several normal tissues and human tumor-derived cell lines.DEVELOPMENTAL STAGE Isoform 1 is activated specifically during the S and G2/M phases of the cell cycle.INDUCTION Up-regulated by IL12 in T-lymphocytes. Up-regulated in subcutaneous adipose tissue of obese individuals.PTM Autophosphorylated (PubMed:8226782, PubMed:1833717). Isoform 1 undergoes phosphorylation mainly on Ser residues, and isoform 2 on both Ser and Thr residues (PubMed:8226782). Phosphorylated on Thr-290; the phosphorylation is necessary but not sufficient for full kinase activity in vitro and for the dissociation of isoform 1 from NFKB1, leading to its degradation (PubMed:15466476, PubMed:15699325). Phosphorylated on Ser-400 by IKBKB; the phosphorylation is required for LPS-stimulated activation of the MAPK/ERK pathway in macrophages (PubMed:17472361, PubMed:22988300).MISCELLANEOUS Can be converted to an oncogenic protein by proviral activation, leading to a C-terminally truncated protein with transforming activity.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.CAUTION A paper describing a role for this protein in IRAK1-independent activation of the MAPK/ERK pathway in response to IL1 has been retracted, because some of the experimental data could not be reproduced.

UniProtP41279

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467

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Reactome DB_ID: 451638

NFKB1:MAP3K8:TNIP2 [cytosol]

NFKB1:MAP3K8:TNIP2

NFKB p105:TPL2:ABIN2

Reactome DB_ID: 451607

EQUAL

968

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome DB_ID: 389388

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467

EQUAL

Reactome Database ID Release 70451638Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451638ReactomeR-HSA-451638

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451638.1Reactome Database ID Release 70451634Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451634ReactomeR-HSA-451634

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451634.315169888Pubmed2004ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stabilityLang, VSymons, AWatton, SJJanzen, JSoneji, YBeinke, SHowell, SLey, SCMol Cell Biol 24:5235-489950430Pubmed1999TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105Belich, MPSalmeron, AJohnston, LHLey, SCNature 397:363-815699325Pubmed2005Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharideCho, JTsichlis, PNProc Natl Acad Sci U S A 102:2350-512832462Pubmed2003NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activityBeinke, SDeka, JLang, VBelich, MPWalker, PAHowell, SSmerdon, SJGamblin, SJLey, SCMol Cell Biol 23:4739-5212667451Pubmed2003NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinaseWaterfield, MRZhang, MNorman, LPSun, SCMol Cell 11:685-94

INHIBITION

Degradation of NFKB p105 frees Tpl2 from p105 allowing it to activate MEK1.

Reactome Database ID Release 70451645Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451645ReactomeR-HSA-451645

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451645.1

Reactome DB_ID: 451619

O-phospho-L-serine at 927

927

EQUAL

O-phospho-L-serine at 932

932

EQUAL

ubiquitinylated lysine at unknown position

EQUAL

968

EQUAL

INHIBITION

Degradation of NFKB p105 frees Tpl2 from p105 allowing it to activate MEK1.

Reactome Database ID Release 705692833Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5692833ReactomeR-HSA-5692833

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5692833.1

Reactome DB_ID: 5684242

3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 [cytosol]

3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2

Reactome DB_ID: 5684259

O-phospho-L-threonine at 290

290

EQUAL

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome DB_ID: 451619

O-phospho-L-serine at 927

927

EQUAL

O-phospho-L-serine at 932

932

EQUAL

ubiquitinylated lysine at unknown position

EQUAL

968

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome Database ID Release 705684242Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684242ReactomeR-HSA-5684242

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684242.2

2.7.11.10

IKBKB phosphorylates TPL2 (MAP3K8) at Ser400

The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation. MAP3K8 undergoes phosphorylated on S400 in its C-terminal tail to activate MAP2Ks (MEK1/2) following LPS stimulation of macrophages. Different experimental systems have suggested that S400 is either autophosphosphorylated by MAPK3P8 (IL-1?-stimulated IL-1R-293T cells) or transphosphorylated by an unknown kinase (LPS-stimulated RAW264.7 macrophages).

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 113592

Reactome DB_ID: 451638

Reactome DB_ID: 5687880

NFKB1:p-S400-MAP3K8:TNIP2 [cytosol]

NFKB1:p-S400-MAP3K8:TNIP2

Reactome DB_ID: 5684308

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome DB_ID: 451607

EQUAL

968

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome Database ID Release 705687880Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5687880ReactomeR-HSA-5687880

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5687880.1

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 177663

GO0008384

GO molecular function

Reactome Database ID Release 70451612Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451612Reactome Database ID Release 705684275Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684275ReactomeR-HSA-5684275

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684275.116806191Pubmed2006Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62Stafford, Margaret JMorrice, Nick APeggie, Mark WCohen, PFEBS Lett. 580:4010-422988300Pubmed2012I?B kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400Roget, KarineBen-Addi, AbduelhakemMambole-Dema, AgnesGantke, ThorstenYang, Huei-TingJanzen, JuliaMorrice, NAbbott, Derek WLey, Steven CMol. Cell. Biol. 32:4684-9019754427Pubmed2009IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2Handoyo, HoseaStafford, Margaret JMcManus, EamonBaltzis, DionissiosPeggie, MarkCohen, PBiochem. J. 424:109-18

MAP3K8 is phosphorylated

TPL2 (MAP3K8) is phosphorylated at T290The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation (Gantke T 2011).The catalytic subunit of MAP3K8 (TPL2) was reported to undergo phosphorylation at Thr290 in human embryonic kidney 293 (HEK293) cells transfected with MAP3K8 (Luciano BS et al. 2004; Cho J et al. 2005; Stafford MJ et al. 2006). Mutation of this residue to alanine prevented the LPS-stimulated activation of MAP3K8 in mouse macrophages (Cho J et al. 2005). Experiments with a small-molecule inhibitor of MAP3K8 have suggested that Thr290 is autophosphosphorylated after IL-1 beta stimulation of IL-1R-expressing HEK293T cells (Handoyo H et al. 2009). However, a catalytically inactive mutant of MAP3K8 (Tpl2-K167M) was reported to become phosphorylated at Thr290 in transfected HEK-293 cells, suggesting that Thr290 phosphorylation did not occur as a result of autophosphorylation (Cho J et al. 2005) In addition, the phosphorylation at Thr290 was also reported to be catalysed by IKBKB, based on small interfering RNA(siRNA)-knockdown studies and the use of high concentrations of the IKBKB inhibitor PS1145 (Cho J et al. 2005). However, the other work showed that lower concentrations of PS1145, but nevertheless sufficient to completely inhibit IKBKB, did not affect the IL-1-stimulated phosphorylation of transfected MAP3K8 at Thr290, suggesting that the IL-1 beta stimulated phosphorylation of Thr290 is catalysed by a protein kinase distinct from IKBKB. (Stafford MJ et al. 2006). Thus, phosphorylation at Thr290 is required for the physiological activation of MAP3K8 by external signals, although the mode of the modification remains to be clarified. Activation of MAP3K8 may also occur trough phosphorylation on Ser62 and Ser400 (Stafford MJ et al. 2006; Roget K et al. 2012).

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 113592

Reactome DB_ID: 451638

Reactome DB_ID: 5684265

NFKB1:p-T290-MAP3K8:TNIP2 [cytosol]

NFKB1:p-T290-MAP3K8:TNIP2

Reactome DB_ID: 5684259

O-phospho-L-threonine at 290

290

EQUAL

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome DB_ID: 451607

EQUAL

968

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome Database ID Release 705684265Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684265ReactomeR-HSA-5684265

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684265.1

Reactome DB_ID: 29370

Reactome Database ID Release 705684261Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684261ReactomeR-HSA-5684261

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684261.215778223Pubmed2005Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Ikappa-B Kinase-beta-dependent pathway and is required for Tpl2 activation by external signalsCho, JeongheeMelnick, MichaelSolidakis, Georgios PTsichlis, Philip NJ. Biol. Chem. 280:20442-815466476Pubmed2004Phosphorylation of threonine 290 in the activation loop of Tpl2/Cot is necessary but not sufficient for kinase activityLuciano, Brenda SHsu, SangChannavajhala, Padma LLin, Lih-LingCuozzo, John WJ. Biol. Chem. 279:52117-2321135874Pubmed2011Regulation and function of TPL-2, an I?B kinase-regulated MAP kinase kinase kinaseGantke, ThorstenSriskantharajah, SrividyaLey, Steven CCell Res. 21:131-45

2.7.11.10

IKBKB phosphorylates NFkB p105 within the NFkB p105:TPL2:ABIN2 complex

NFkappaB p105 protein (p105) is a precursor of the NFkappaB p50 subunit and an inhibitor of NFkappaB. The IkappaB kinase (IKK) complex phosphorylates p105 on S927 within the PEST region. TNF-alpha-induced p105 proteolysis additionally requires the phosphorylation of S932. Purified IKK (IKK1) or IKKB (IKK2) can phosphorylate both these regulatory serines in vitro.

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 113592

Reactome DB_ID: 451638

Reactome DB_ID: 5687885

p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2 [cytosol]

p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2

Reactome DB_ID: 451611

O-phospho-L-serine at 927

927

EQUAL

O-phospho-L-serine at 932

932

EQUAL

968

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome DB_ID: 389388

EQUAL

467

EQUAL

Reactome Database ID Release 705687885Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5687885ReactomeR-HSA-5687885

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5687885.1

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 177663

Reactome Database ID Release 705684267Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684267ReactomeR-HSA-5684267

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684267.112482991Pubmed2003betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932Lang, VJanzen, JFischer, GZSoneji, YBeinke, SSalmeron, AAllen, HHay, RTBen-Neriah, YLey, SCMol Cell Biol 23:402-13

SCF betaTrCP1,2 binds p-NFkB p105:TPL2:ABIN2

IKK-mediated NFkB p105 phosphorylation generates a binding site for betaTrCP, the receptor subunit of the SCF-type beta-TrCP ubiquitin E3 ligase complex.

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 5684268

p-S927,S932-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 [cytosol]

p-S927,S932-NFKB1(1-968):p-S,T-MAP3K8:TNIP2

Reactome DB_ID: 5684259

O-phospho-L-threonine at 290

290

EQUAL

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome DB_ID: 451611

O-phospho-L-serine at 927

927

EQUAL

O-phospho-L-serine at 932

932

EQUAL

968

EQUAL

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome Database ID Release 705684268Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684268ReactomeR-HSA-5684268

Reactome DB_ID: 1168601

(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1) [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 5684270

SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2 [cytosol]

SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2

Reactome DB_ID: 5684268

Converted from EntitySet in Reactome

Reactome DB_ID: 1168601

Reactome Database ID Release 705684270Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684270ReactomeR-HSA-5684270

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684270.1Reactome Database ID Release 705684248Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684248ReactomeR-HSA-5684248

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684248.114673179Pubmed2004Dual effects of IkappaB kinase beta-mediated phosphorylation on p105 Fate: SCF(beta-TrCP)-dependent degradation and SCF(beta-TrCP)-independent processingCohen, SAchbert-Weiner, HCiechanover, AMol Cell Biol 24:475-8611158290Pubmed2001Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalphaHeissmeyer, VKrappmann, DHatada, E NScheidereit, CMol. Cell. Biol. 21:1024-35

6.3.2.19

SCF betaTrCP ubiquitinates NFKB p105 within p-S927, S932-NFkB p105:TPL2:ABIN2

Beta-TrCP ubiquitinates p105 at several lysine residues within the C-terminal region 660-968. The level of ubiquitination is variable; in this reaction p105 is represented with 3 ubiquitinated lysine residues. Removal of all lysines within this region abolishes subsequent p105 degradation.

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 5684270

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Converted from EntitySet in Reactome

Reactome DB_ID: 1168601

Reactome DB_ID: 5684242

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 5684270

Reactome Database ID Release 705687862Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5687862Reactome Database ID Release 705684250Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684250ReactomeR-HSA-5684250

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684250.3

3xUb,p-S-NFkB p105:TPL2:ABIN2 dissociates due to degradation of p105

IKBKB-induced proteolysis of NFkB p105 to p50 releases MAP3K8 (TPL2) from the complex with NFkB p105 and ABIN2. On TLR or IL1beta stimulation, dissociated MAP3K8 with an adequate phosphorylation state activates MAP2K (MKK1/2) and consequently MAPK1/3 (ERK1/2).

Authored: Shamovsky, Veronica, 2015-05-12Reviewed: Jupe, Steve, 2015-04-14Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Shamovsky, Veronica, 2015-08-25

Reactome DB_ID: 5684242

Reactome DB_ID: 5684259

O-phospho-L-threonine at 290

290

EQUAL

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 451661

EQUAL

429

EQUAL

Reactome Database ID Release 705684273Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684273ReactomeR-HSA-5684273

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684273.1

2.7.11.25

TPL2 phosphorylates MEK1, SEK1

Tpl2 (also known as Cot, officially known as MAP3K8) is constitutively bound to NFKB p105 (p105) which inhibits its MEK kinase activity in resting cells. Proteolysis of p105 frees Tpl2 from p105 and allows subsequent phosphorylation and activation of MEK1. Tpl2 can also activate SEK1 (MAP2K4). Phosphorylation of Tpl-2 is believed to play a role in its activation (Cho et al, 2005; Robinson et al. 2007). Positions of phosphorylations represented here are inferred from general experimental data (Zheng & Guan, 1994).

Authored: Ray, KP, 2010-05-17Reviewed: Pinteaux, E, 2010-05-17Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20Edited: Jupe, S, 2010-05-17

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 451647

MAP2K1,MAP2K4 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAP2K4 [cytosol]MAP2K1 [cytosol]

UniProtQ02750Converted from EntitySet in Reactome

Reactome DB_ID: 451654

p-S218,S222-MAP2K1,p-S257,T261-MAP2K4 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S257,T261-MAP2K4 [cytosol]p-S218,S222-MAP2K1 [cytosol]

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 5684259

O-phospho-L-threonine at 290

290

EQUAL

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

Reactome Database ID Release 70451651Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451651Reactome Database ID Release 70451649Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451649ReactomeR-HSA-451649

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451649.317709378Pubmed2007Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extracellular signal-regulated kinase in macrophagesRobinson, MJBeinke, SKouroumalis, ATsichlis, PNLey, SCMol Cell Biol 27:7355-648131746Pubmed1994Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residuesZheng, CFGuan, KLEMBO J 13:1123-31

Reactome Database ID Release 705684264Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684264ReactomeR-HSA-5684264

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684264.217848581Pubmed2007Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and bloodHall, J PerryKurdi, YahyaHsu, SangCuozzo, JohnLiu, JulieTelliez, Jean-BaptisteSeidl, Katherine JWinkler, AaronHu, YonghanGreen, NealAskew, G RogerTam, SteveClark, James DLin, Lih-LingJ. Biol. Chem. 282:33295-30421469113Pubmed2011Cot/tpl2 activity is required for TLR-induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expressionLópez-Peláez, MartaSoria-Castro, IreneBoscá, LisardoFernández, MargaritaAlemany, SusanaEur. J. Immunol. 41:1733-4120606319Pubmed2010Inhibition of tumor progression locus 2 protein kinase decreases lipopolysaccharide-induced tumor necrosis factor alpha production due to the inhibition of the tip-associated protein induction in RAW264.7 cellsHirata, KazuyaMiyashiro, MasahikoOgawa, HirofumiTaki, HirofumiTobe, KazuyukiSugita, TakahisaBiol. Pharm. Bull. 33:1233-721377269Pubmed2011Tpl2 kinase signal transduction in inflammation and cancerVougioukalaki, MariaKanellis, Dimitris CGkouskou, KalliopiEliopoulos, Aristides GCancer Lett. 304:80-912234923Pubmed2002Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signalsEliopoulos, Aristides GDumitru, Calin DWang, Chun-ChiCho, JeongheeTsichlis, Philip NEMBO J. 21:4831-4010072079Pubmed1999The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinasesLin, XCunningham, E TMu, YGeleziunas, RGreene, W CImmunity 10:271-8022733995Pubmed2012Coordinate regulation of TPL-2 and NF-?B signaling in macrophages by NF-?B1 p105Yang, Huei-TingPapoutsopoulou, StamatiaBelich, MonicaBrender, ChristineJanzen, JuliaGantke, ThorstenHandley, MattLey, Steven CMol. Cell. Biol. 32:3438-5111163183Pubmed2000TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathwayDumitru, C DCeci, J DTsatsanis, CKontoyiannis, DStamatakis, KLin, J HPatriotis, CJenkins, N ACopeland, N GKollias, GTsichlis, P NCell 103:1071-83978-953-51-0633-3ISBN2012The Role of Tpl2 Protein Kinase in Carcinogenesis and InflammationDeCicco-Skinner, Kathleen L.Deshpande, MonikaWiest, JonathanAdvances in Protein Kinases (Book)19414798Pubmed2009Adiponectin promotes endotoxin tolerance in macrophages by inducing IRAK-M expressionZacharioudaki, VassilikiAndroulidaki, AriadneArranz, AliciaVrentzos, GeorgeMargioris, Andrew NTsatsanis, ChristosJ. Immunol. 182:6444-5115485931Pubmed2004Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NF-kappaB1 p105Beinke, SRobinson, M JHugunin, MLey, S CMol. Cell. Biol. 24:9658-6719933865Pubmed2009Tumor progression locus 2 (Map3k8) is critical for host defense against Listeria monocytogenes and IL-1 beta productionMielke, Lisa AElkins, Karen LWei, LaiStarr, RobynTsichlis, Philip NO'Shea, John JWatford, Wendy TJ. Immunol. 183:7984-93

MAPK targets/ Nuclear events mediated by MAP kinases

MAPKs are protein kinases that, once activated, phosphorylate their specific cytosolic or nuclear substrates at serine and/or threonine residues. Such phosphorylation events can either positively or negatively regulate substrate, and thus entire signaling cascade activity. The major cytosolic target of activated ERKs are RSKs (90 kDa Ribosomal protein S6 Kinase). Active RSKs translocates to the nucleus and phosphorylates such factors as c-Fos(on Ser362), SRF (Serum Response Factor) at Ser103, and CREB (Cyclic AMP Response Element-Binding protein) at Ser133. In the nucleus activated ERKs phosphorylate many other targets such as MSKs (Mitogen- and Stress-activated protein kinases), MNK (MAP interacting kinase) and Elk1 (on Serine383 and Serine389). ERK can directly phosphorylate CREB and also AP-1 components c-Jun and c-Fos. Another important target of ERK is NF-KappaB. Recent studies reveals that nuclear pore proteins are direct substrates for ERK (Kosako H et al, 2009). Other ERK nuclear targets include c-Myc, HSF1 (Heat-Shock Factor-1), STAT1/3 (Signal Transducer and Activator of Transcription-1/3), and many more transcription factors.Activated p38 MAPK is able to phosphorylate a variety of substrates, including transcription factors STAT1, p53, ATF2 (Activating transcription factor 2), MEF2 (Myocyte enhancer factor-2), protein kinases MSK1, MNK, MAPKAPK2/3, death/survival molecules (Bcl2, caspases), and cell cycle control factors (cyclin D1).JNK, once activated, phosphorylates a range of nuclear substrates, including transcription factors Jun, ATF, Elk1, p53, STAT1/3 and many other factors. JNK has also been shown to directly phosphorylate many nuclear hormone receptors. For example, peroxisome proliferator-activated receptor 1 (PPAR-1) and retinoic acid receptors RXR and RAR are substrates for JNK. Other JNK targets are heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Other adaptor and scaffold proteins have also been characterized as nonnuclear substrates of JNK.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

ERK/MAPK targets

ERK/MAPK kinases have a number of targets within the nucleus, usually transcription factors or other kinases. The best known targets, ELK1, ETS1, ATF2, MITF, MAPKAPK2, MSK1, RSK1/2/3 and MEF2 are annotated here.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

2.7.11

ERK1/2 activates ELK1

Following translocation to the nucleus, ERK1/2 directly phosphorylates key effectors, including the ubiquitous transcription factors ELK1 (Ets like protein 1). At least five residues in the C terminal domain of ELK1 are phosphorylated upon stimulation with growth factor stimulation. ELK1 can form a ternary complex with the serum response factor (SRF) and consensus sequences, such as serum response elements (SRE), on DNA, thus stimulating transcription of a set of immediate early genes like FOS (c-fos) (Marais et al, 1993; Gille et al, 1995; Duan et al, 1998; reviewed in Treisman, 1995).

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Reactome DB_ID: 3009346

UniProt:P19419 ELK1

ELK1

ELK1FUNCTION Transcription factor that binds to purine-rich DNA sequences. Forms a ternary complex with SRF and the ETS and SRF motifs of the serum response element (SRE) on the promoter region of immediate early genes such as FOS and IER2. Induces target gene transcription upon JNK-signaling pathway stimulation (By similarity).SUBUNIT Interacts in its sumoylated form with PIAS2/PIASX which enhances its transcriptional activator activity (PubMed:15920481). Interacts with MAD2L2; the interaction is direct and promotes phosphorylation by the kinases MAPK8 and/or MAPK9 (PubMed:17296730). Interacts with POU1F1 (PubMed:26612202).TISSUE SPECIFICITY Lung and testis.PTM Sumoylation represses transcriptional activator activity as it results in recruitment of HDAC2 to target gene promoters which leads to decreased histone acetylation and reduced transactivator activity. It also regulates nuclear retention.PTM On mitogenic stimulation, phosphorylated on C-terminal serine and threonine residues by MAPK1. Ser-383 and Ser-389 are the preferred sites for MAPK1. In vitro, phosphorylation by MAPK1 potentiates ternary complex formation with the serum responses factors, SRE and SRF. Also phosphorylated on Ser-383 by MAPK8 and/or MAKP9. Phosphorylation leads to loss of sumoylation and restores transcriptional activator activity. Phosphorylated and activated by CAMK4, MAPK11, MAPK12 and MAPK14. Upon bFGF stimulus, phosphorylated by PAK1 (By similarity).SIMILARITY Belongs to the ETS family.

UniProtP19419

EQUAL

428

EQUAL

Reactome DB_ID: 113582

Reactome DB_ID: 3009350

O-phospho-L-serine at 324

324

EQUAL

O-phospho-L-serine at 383

383

EQUAL

O-phospho-L-serine at 389

389

EQUAL

O-phospho-L-serine at 422

422

EQUAL

O-phospho-L-threonine at 336

336

EQUAL

428

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 198701

p-T,Y MAPK dimers [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 70198713Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198713Reactome Database ID Release 70198731Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198731ReactomeR-HSA-198731

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198731.311145955Pubmed2001Estrogen receptor-mediated activation of the serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1Duan, RenqinXie, WenBurghardt, Robert CSafe, StephenJ. Biol. Chem. 276:11590-88386592Pubmed1993The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domainMarais, RWynne, JudyTreisman, RichardCell 73:381-937588619Pubmed1995Journey to the surface of the cell: Fos regulation and the SRETreisman, RichardEMBO J. 14:4905-137889942Pubmed1995ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivationGille, HKortenjann, MThomae, OMoomaw, CSlaughter, CCobb, MHShaw, PEEMBO J 14:951-62

2.7.11

ERK1/2 phosphorylates MSK1

MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by ERK1/2 through phosphorylation at four key residues.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Reactome DB_ID: 198657

UniProt:O75582 RPS6KA5

RPS6KA5

RPS6KA5MSK1FUNCTION Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factors RELA, STAT3 and ETV1/ER81, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes (PubMed:11909979, PubMed:12569367, PubMed:12763138, PubMed:9687510, PubMed:18511904, PubMed:9873047). Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin (PubMed:11909979, PubMed:9873047). Plays an essential role in the control of RELA transcriptional activity in response to TNF and upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 and contributes to RELA inhibition and repression of inflammatory gene expression (PubMed:12628924, PubMed:18511904). In skeletal myoblasts is required for phosphorylation of RELA at 'Ser-276' during oxidative stress (PubMed:12628924). In erythropoietin-stimulated cells, is necessary for the 'Ser-727' phosphorylation of STAT3 and regulation of its transcriptional potential (PubMed:12763138). Phosphorylates ETV1/ER81 at 'Ser-191' and 'Ser-216', and thereby regulates its ability to stimulate transcription, which may be important during development and breast tumor formation (PubMed:12569367). Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A (PubMed:15010469). Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN (PubMed:12773393). May also phosphorylate 'Ser-28' of histone H3 (PubMed:12773393). Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14) (PubMed:12773393). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines (By similarity). Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors (By similarity). Plays a role in neuronal cell death by mediating the downstream effects of excitotoxic injury (By similarity). Phosphorylates TRIM7 at 'Ser-107' in response to growth factor signaling via the MEK/ERK pathway, thereby stimulating its ubiquitin ligase activity (PubMed:25851810).ACTIVITY REGULATION Activated by phosphorylation at Ser-360, Thr-581 and Thr-700 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha, and by further autophosphorylation of Ser-212, Ser-376 and Ser-381 by the activated C-terminal kinase domain. The active N-terminal kinase domain finally phosphorylates downstream substrates, as well as Ser-750, Ser-752 and Ser-758 in its own C-terminal region.SUBUNIT Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells which transiently dissociates following mitogenic stimulation. Also associates with MAPK14/p38-alpha. Activated RPS6KA5 associates with and phosphorylates the NF-kappa-B p65 subunit RELA. Interacts with CREBBP and EP300.TISSUE SPECIFICITY Widely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver.PTM Ser-376 and Thr-581 phosphorylation is required for kinase activity. Ser-376 and Ser-212 are autophosphorylated by the C-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain. Phosphorylated at Ser-360, Thr-581 and Thr-700 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha. Autophosphorylated at Ser-750, Ser-752 and Ser-758 by the N-terminal kinase domain.PTM Ubiquitinated.MISCELLANEOUS Enzyme activity requires the presence of both kinase domains.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily.

UniProtO75582

EQUAL

802

EQUAL

Reactome DB_ID: 113582

Reactome DB_ID: 198683

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 581

581

EQUAL

O-phospho-L-serine at 360

360

EQUAL

O-phospho-L-serine at 212

212

EQUAL

802

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 198701

Reactome Database ID Release 70198756Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198756ReactomeR-HSA-198756

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198756.39687510Pubmed1998Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREBDeak, MClifton, ADLucocq, LMAlessi, DREMBO J 17:4426-41

2.7.11

p38MAPK phosphorylates MSK1

MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by p38MAPK through phosphorylation at four key residues.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Reactome DB_ID: 198657

EQUAL

802

EQUAL

Reactome DB_ID: 113582

Reactome DB_ID: 198683

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 581

581

EQUAL

O-phospho-L-serine at 360

360

EQUAL

O-phospho-L-serine at 212

212

EQUAL

802

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 198703

Reactome Database ID Release 70198647Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198647Reactome Database ID Release 70198669Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198669ReactomeR-HSA-198669

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198669.1

2.7.11

ERK1/2/5 activate RSK1/2/3

The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK. RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398. Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37Edited: D'Eustachio, P, 2013-07-15Edited: Matthews, L, 2013-07-15

Reactome DB_ID: 29358

Converted from EntitySet in Reactome

Reactome DB_ID: 199858

Ribosomal protein S6 kinase [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPS6KA1 [nucleoplasm]RPS6KA3 [nucleoplasm]RPS6KA2 [nucleoplasm]

UniProtQ15418UniProtP51812UniProtQ15349Converted from EntitySet in Reactome

Reactome DB_ID: 199849

Phospho-Ribosomal protein S6 kinase [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-4S,T231,T365-RPS6KA3 [nucleoplasm]p-4S,T356,T570-RPS6KA2 [nucleoplasm]p-4S,T359,T573-RPS6KA1 [nucleoplasm]

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 199878

p-MAPK3/MAPK1/MAPK7 dimers [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 70199864Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199864Reactome Database ID Release 70198746Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198746ReactomeR-HSA-198746

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198746.316626623Pubmed2006The MAP kinase ERK5 binds to and phosphorylates p90 RSKRanganathan, APearson, GWChrestensen, CASturgill, TWCobb, MHArch Biochem Biophys 449:8-1612832467Pubmed2003Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activityRoux, PPRichards, SABlenis, JMol Cell Biol 23:4796-804

2.7.11

ERK5 activates the transcription factor MEF2

The MEF2 (Myocyte-specific enhancer factor 2) proteins constitute a family of transcription factors: MEF2A, MEF2B, MEF2C, and MEF2D. MEF2A and MEF2C are known substrates of ERK5, and their transactivating activity can be stimulated by ERK5 via direct phosphorylation. MEF2A and MEF2C are expressed in developing and adult brain including cortex and cerebellum.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Converted from EntitySet in Reactome

Reactome DB_ID: 199911

MEF2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMEF2A [nucleoplasm]MEF2C [nucleoplasm]

UniProtQ02078UniProtQ06413Converted from EntitySet in Reactome

Reactome DB_ID: 199933

p-MEF2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S408-MEF2A [nucleoplasm]p-S396-MEF2C [nucleoplasm]

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 198738

UniProt:Q13164 MAPK7

MAPK7

MAPK7ERK5BMK1PRKM7FUNCTION Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras-independent and MAP2K5-dependent pathway. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction.ACTIVITY REGULATION Activated by tyrosine and threonine phosphorylation (By similarity). Activated in response to hyperosmolarity, hydrogen peroxide, and epidermal growth factor (EGF).SUBUNIT Interacts with MAP2K5. Forms oligomers (By similarity). Interacts with MEF2A, MEF2C and MEF2D; the interaction phosphorylates the MEF2s and enhances transcriptional activity of MEF2A, MEF2C but not MEF2D (By similarity). Interacts with SGK1. Preferentially interacts with PML isoform PML-4 but shows interaction also with its other isoforms: isoform PML-1, isoform PML-2, isoform PML-3 and isoform PML-6. Interacts (via N-terminal half) with HSP90AB1-CDC37 chaperone complex in resting cells; the interaction is MAP2K5-independent and prevents MAPK7 from ubiquitination and proteasomal degradation (PubMed:23428871).TISSUE SPECIFICITY Expressed in many adult tissues. Abundant in heart, placenta, lung, kidney and skeletal muscle. Not detectable in liver.DOMAIN The second proline-rich region may interact with actin targeting the kinase to a specific location in the cell.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-219 and Tyr-221, which activates the enzyme (By similarity). Autophosphorylated in vitro on threonine and tyrosine residues when the C-terminal part of the kinase, which could have a regulatory role, is absent.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.

UniProtQ13164

O-phospho-L-threonine at 218

218

EQUAL

O4'-phospho-L-tyrosine at 220

220

EQUAL

O4'-phospho-L-tyrosine [MOD:00048]

EQUAL

816

EQUAL

Reactome Database ID Release 70199939Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199939Reactome Database ID Release 70199929Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199929ReactomeR-HSA-199929

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199929.1

ERKs are inactivated by protein phosphatase 2A

ERKs are inactivated by the protein phosphatase 2A (PP2A). The PP2A holoenzyme is a heterotrimer that consists of a core dimer, composed of a scaffold (A) and a catalytic (C) subunit that associates with a variety of regulatory (B) subunits. The B subunits have been divided into gene families named B (or PR55), B0 (or B56 or PR61) and B00 (or PR72). Each family comprises several members. B56 family members of PP2A in particular, increase ERK dephosphorylation, without affecting its activation by MEK. Induction of PP2A is involved in the extracellular signal-regulated kinase (ERK) signalling pathway, in which it provides a feedback control, as well as in a broad range of other cellular processes, including transcriptional regulation and control of the cell cycle.This diversity of functions is conferred by a diversity of regulatory subunits, the combination of which can give rise to over 50 different forms of PP2A. For example, five distinct mammalian genes encode members of the B56 family, called B56a, b, g, d and e, generating at least eight isoforms. Whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Converted from EntitySet in Reactome

Reactome DB_ID: 199878

Reactome DB_ID: 113518

water [ChEBI:15377]

water

ChEBI15377

Reactome DB_ID: 113550

phosphate(3-) [ChEBI:18367]

phosphate(3-)

ChEBI18367Converted from EntitySet in Reactome

Reactome DB_ID: 199955

MAPK3/MAPK1/MAPK7 dimers [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 165970

PP2A-ABdeltaC complex [nucleoplasm]

PP2A-ABdeltaC complex

Converted from EntitySet in Reactome

Reactome DB_ID: 165974

PP2A-catalytic subunit C [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Converted from EntitySet in Reactome

Reactome DB_ID: 165997

PP2A-subunit A [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 3008956

UniProt:Q14738 PPP2R5D

PPP2R5D

PPP2R5DFUNCTION The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment.SUBUNIT PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with SGO1. Interacts with ADCY8 (PubMed:22976297).TISSUE SPECIFICITY Isoform Delta-2 is widely expressed. Isoform Delta-1 is highly expressed in brain.INDUCTION By retinoic acid; in neuroblastoma cell lines.SIMILARITY Belongs to the phosphatase 2A regulatory subunit B56 family.

UniProtQ14738

EQUAL

602

EQUAL

Reactome Database ID Release 70165970Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165970ReactomeR-HSA-165970

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165970.1GO0004722

GO molecular function

Reactome Database ID Release 70199956Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199956Reactome Database ID Release 70199959Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199959ReactomeR-HSA-199959

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199959.116456541Pubmed2006B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERKLetourneux, CRocher, GPorteu, FEMBO J 25:727-38

ERKs are inactivated

MAP Kinases are inactivated by a family of protein named MAP Kinase Phosphatases (MKPs). They act through dephosphorylation of threonine and/or tyrosine residues within the signature sequence -pTXpY- located in the activation loop of MAP kinases (pT=phosphothreonine and pY=phosphotyrosine). MKPs are divided into three major categories depending on their preference for dephosphorylating; tyrosine, serine/threonine and both the tyrosine and threonine (dual specificity phoshatases or DUSPs). The tyrosine-specific MKPs include PTP-SL, STEP and HePTP, serine/threonine-specific MKPs are PP2A and PP2C, and many DUSPs acting on MAPKs are known. Activated MAP kinases trigger activation of transcription of MKP genes. Therefore, MKPs provide a negative feedback regulatory mechanism on MAPK signaling, by inactivating MAPKs via dephosphorylation, in the cytoplasm and the nucleus. Some MKPs are more specific for ERKs, others for JNK or p38MAPK.

Reviewed: Greene, LA, 2007-11-08 15:39:37

3.1.3.48

ERKs are inactivated by dual-specific phosphatases (DUSPs)

Over 10 dual specificity phosphatases (DUSPs) active on MAP kinases are known. Among them, some possess good ERK docking sites and so are more specific for the ERKS (DUSP 3, 4, 6, 7), others are more specific for p38MAPK (DUSP1 and 10), while others do not seem to discriminate. It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. Moreover, differential activation of DUSPs by different stimuli is thought to contribute to pathway specificity.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37Edited: Jassal, B, 2010-11-17

Converted from EntitySet in Reactome

Reactome DB_ID: 199878

Reactome DB_ID: 113518

Reactome DB_ID: 113550

Converted from EntitySet in Reactome

Reactome DB_ID: 199955

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 203792

ERK-specific DUSP [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDUSP7 [nucleoplasm]DUSP4 [nucleoplasm]DUSP3 [nucleoplasm]DUSP6 [nucleoplasm]

UniProtQ16829UniProtQ13115UniProtP51452UniProtQ16828GO0004725

GO molecular function

Reactome Database ID Release 70203785Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203785Reactome Database ID Release 70203797Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203797ReactomeR-HSA-203797

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203797.217322878Pubmed2007A module of negative feedback regulators defines growth factor signalingAmit, ICitri, AShay, TLu, YKatz, MZhang, FTarcic, GSiwak, DLahad, JJacob-Hirsch, JAmariglio, NVaisman, NSegal, ERechavi, GAlon, UMills, GBDomany, EYarden, YNat Genet 39:503-12

INHIBITION

Reactome Database ID Release 708942517Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8942517ReactomeR-HSA-8942517

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8942517.1

Reactome DB_ID: 8942511

VRK3:DUSP3 [nucleoplasm]

VRK3:DUSP3

Reactome DB_ID: 8942507

UniProt:Q8IV63 VRK3

VRK3

VRK3FUNCTION Inactive kinase that suppresses ERK activity by promoting phosphatase activity of DUSP3 which specifically dephosphorylates and inactivates ERK in the nucleus.SUBUNIT Interacts with DUSP3 (By similarity). Interacts with RAN.SIMILARITY Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. VRK subfamily.CAUTION Inactive as a kinase due to its inability to bind ATP.

UniProtQ8IV63

EQUAL

474

EQUAL

Reactome DB_ID: 203798

UniProt:P51452 DUSP3

DUSP3

VHRDUSP3FUNCTION Shows activity both for tyrosine-protein phosphate and serine-protein phosphate, but displays a strong preference toward phosphotyrosines. Specifically dephosphorylates and inactivates ERK1 and ERK2.SUBUNIT Interacts with VRK3, which seems to activate it's phosphatase activity.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class dual specificity subfamily.

EQUAL

185

EQUAL

Reactome Database ID Release 708942511Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8942511ReactomeR-HSA-8942511

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8942511.1

Reactome Database ID Release 70202670Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202670ReactomeR-HSA-202670

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202670.215115656Pubmed2004Structure and regulation of MAPK phosphatasesFarooq, AZhou, MMCell Signal 16:769-79

Reactome Database ID Release 70198753Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198753ReactomeR-HSA-198753

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198753.1

CREB phosphorylation

Nerve growth factor (NGF) activates multiple signalling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133. CREB phosphorylation at serine 133 is a crucial event in neurotrophin signalling, being mediated by ERK/RSK, ERK/MSK1 and p38/MAPKAPK2 pathways. Several kinases, such as MSK1, RSK1/2/3 (MAPKAPK1A/B/C), and MAPKAPK2, are able to directly phosphorylate CREB at S133. MSK1 is also able to activate ATF (Cyclic-AMP-dependent transcription factor). However, the NGF-induced CREB phosphorylation appears to correlate better with activation of MSK1 rather than RSK1/2/3, or MAPKAPK2. In retrograde signalling, activation of CREB occurs within 20 minutes after neurotrophin stimulation of distal axons.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

2.7.11

MSK1 activates CREB

MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB).

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Reactome DB_ID: 52777

UniProt:P16220 CREB1

CREB1

CREB1FUNCTION Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-133 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.SUBUNIT Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When phosphorylated on Ser-133, binds CREBBP (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity (By similarity). Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-133 (PubMed:15964553).SUBUNIT (Microbial infection) Interacts with hepatitis B virus/HBV protein X.SUBUNIT (Microbial infection) Interacts with HTLV-1 protein Tax.PTM Stimulated by phosphorylation. Phosphorylation of both Ser-133 and Ser-142 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-133 allows CREBBP binding. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). CREBL2 positively regulates phosphorylation at Ser-133 thereby stimulating CREB1 transcriptional activity (By similarity). Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-133. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-142. Phosphorylation of Ser-142 blocks CREB-mediated transcription even when Ser-133 is phosphorylated. Phosphorylated by CaMK1 (By similarity). Phosphorylation of Ser-271 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-133 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. Phosphorylated by TSSK4 on Ser-133 (PubMed:15964553).PTM Sumoylated with SUMO1. Sumoylation on Lys-304, but not on Lys-285, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization.DISEASE A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia.SIMILARITY Belongs to the bZIP family.

UniProtP16220

EQUAL

341

EQUAL

Reactome DB_ID: 113582

Reactome DB_ID: 111910

O-phospho-L-serine at 133

133

EQUAL

341

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 198683

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 581

581

EQUAL

O-phospho-L-serine at 360

360

EQUAL

O-phospho-L-serine at 212

212

EQUAL

802

EQUAL

Reactome Database ID Release 70199934Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199934Reactome Database ID Release 70199935Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199935ReactomeR-HSA-199935

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199935.1

2.7.11

MSK1 activates ATF1

Cyclic-AMP-dependent transcription factor 1 (ATF1) can be phosphorylated at Serine 63 by MSK1, thus activating it.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Reactome DB_ID: 199900

UniProt:P18846 ATF1

ATF1

ATF1FUNCTION This protein binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Binds to the Tax-responsive element (TRE) of HTLV-I. Mediates PKA-induced stimulation of CRE-reporter genes. Represses the expression of FTH1 and other antioxidant detoxification genes. Triggers cell proliferation and transformation.SUBUNIT Binds DNA as a dimer. Interacts with HIPK2 and CDK3.PTM Phosphorylated at Ser-198 by HIPK2 in response to genotoxic stress. This phosphorylation promotes transcription repression of FTH1 and other antioxidant detoxification genes. The CDK3-mediated phosphorylation at Ser-63 promotes its transactivation and transcriptional activities. Phosphorylated at Ser-63 by RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli.SIMILARITY Belongs to the bZIP family. ATF subfamily.

UniProtP18846

EQUAL

271

EQUAL

Reactome DB_ID: 199897

O-phospho-L-serine at 63

EQUAL

271

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 198683

O-phospho-L-serine at 376

376

EQUAL

O-phospho-L-threonine at 581

581

EQUAL

O-phospho-L-serine at 360

360

EQUAL

O-phospho-L-serine at 212

212

EQUAL

802

EQUAL

Reactome Database ID Release 70199910Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199910ReactomeR-HSA-199910

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199910.212414794Pubmed2002ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth factor-induced c-jun expressionGupta, PankajPrywes, RonJ. Biol. Chem. 277:50550-6

2.7.11

RSK1/2/3 phosphorylates CREB at Serine 133

CREB is phosphorylated at Serine 133 by RSK1/2/3.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Reactome DB_ID: 52777

EQUAL

341

EQUAL

Reactome DB_ID: 113582

Reactome DB_ID: 111910

O-phospho-L-serine at 133

133

EQUAL

341

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 199849

Reactome Database ID Release 70199892Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199892Reactome Database ID Release 70199895Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199895ReactomeR-HSA-199895

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199895.19770464Pubmed1998Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos geneDe Cesare, DJacquot, SHanauer, ASassone-Corsi, PProc Natl Acad Sci U S A 95:12202-7

2.7.11

MAPKAPK2 phosphorylates CREB at Serine 133

p38 MAPK activation leads to CREB Serine 133 phosphorylation through the activation of MAPKAP kinase 2 or the closely related MAPKAP kinase 3.

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37

Reactome DB_ID: 29358

Reactome DB_ID: 52777

EQUAL

341

EQUAL

Reactome DB_ID: 113582

Reactome DB_ID: 111910

O-phospho-L-serine at 133

133

EQUAL

341

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 199936

UniProt:P49137 MAPKAPK2

MAPKAPK2

MAPKAPK2FUNCTION Stress-activated serine/threonine-protein kinase involved in cytokine production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the interaction with HSP90 proteins and inhibiting HSF1 homotrimerization, DNA-binding and transactivation activities (PubMed:16278218). Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to the dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impairment of their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to the regulation of the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity, leading to inhibition of dependent degradation of ARE-containing transcripts. Phosphorylates CEP131 in response to cellular stress induced by ultraviolet irradiation which promotes binding of CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar satellites (PubMed:26616734). Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.ACTIVITY REGULATION Activated following phosphorylation by p38-alpha/MAPK14 following various stresses. Inhibited following sumoylation. Specifically inhibited by pyrrolopyridine inhibitors.SUBUNIT Heterodimer with p38-alpha/MAPK14; this heterodimer forms a stable complex: molecules are positioned 'face to face' so that the ATP-binding sites of both kinases are at the heterodimer interface (PubMed:12171911, PubMed:17576063, PubMed:17255097, PubMed:17480064, PubMed:17449059, PubMed:17395714). Interacts with PHC2 (PubMed:15094067). Interacts with HSF1 (PubMed:16278218).TISSUE SPECIFICITY Expressed in all tissues examined.PTM Sumoylation inhibits the protein kinase activity.PTM Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-222, Ser-272 and Thr-334.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.

O-phospho-L-threonine at 222

222

EQUAL

O-phospho-L-serine at 272

272

EQUAL

400

EQUAL

Reactome Database ID Release 70199915Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199915Reactome Database ID Release 70199917Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199917ReactomeR-HSA-199917

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199917.27551568Pubmed1995Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signalsBonni, AGinty, D DDudek, HGreenberg, M EMol. Cell. Neurosci. 6:168-83

Reactome Database ID Release 70199920Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199920ReactomeR-HSA-199920

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199920.1

Activation of the AP-1 family of transcription factors

Activator protein-1 (AP-1) is a collective term referring to a group of transcription factors that bind to promoters of target genes in a sequence-specific manner. AP-1 family consists of hetero- and homodimers of bZIP (basic region leucine zipper) proteins, mainly of Jun-Jun, Jun-Fos or Jun-ATF. AP-1 members are involved in the regulation of a number of cellular processes including cell growth, proliferation, survival, apoptosis, differentiation, cell migration. The ability of a single transcription factor to determine a cell fate critically depends on the relative abundance of AP-1 subunits, the composition of AP-1 dimers, the quality of stimulus, the cell type, the co-factor assembly. AP-1 activity is regulated on multiple levels; transcriptional, translational and post-translational control mechanisms contribute to the balanced production of AP-1 proteins and their functions. Briefly, regulation occurs through:<ol><li>effects on jun, fos, atf gene transcription and mRNA turnover.<li> AP-1 protein members turnover. <li>post-translational modifications of AP-1 proteins that modulate their transactivation potential (effect of protein kinases or phosphatases).<li>interactions with other transcription factors that can either induce or interfere with AP-1 activity.</ol>

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

2.7.11

Phosphorylated MAPKs phosphorylate ATF-2

At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'ATF-2' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'ATF-2-P' are present. This reaction is mediated by the 'protein kinase activity' of 'MAPK1-P'. the Raf–MEK–ERK pathway induces phosphorylation of ATF2 Thr71, whereas subsequent ATF2 Thr69 phosphorylation requires the Ral–RalGDS–Src–p38 pathway. Cooperation between ERK and p38 was found to be essential for ATF2 activation by these mitogens; the activity of p38 and JNK/SAPK in growth factor-stimulated fibroblasts is insufficient to phosphorylate ATF2 Thr71 or Thr69 + 71 significantly by themselves, while ERK cannot dual phosphorylate ATF2 Thr69 + 71 efficiently.

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gay, NJ, 2006-04-24 16:48:17Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 29358

Reactome DB_ID: 450336

UniProt:P15336 ATF2

ATF2

CREB2ATF2CREBP1FUNCTION Transcriptional activator which regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response. Dependent on its binding partner, binds to CRE (cAMP response element) consensus sequences (5'-TGACGTCA-3') or to AP-1 (activator protein 1) consensus sequences (5'-TGACTCA-3'). In the nucleus, contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. In the cytoplasm, interacts with and perturbs HK1- and VDAC1-containing complexes at the mitochondrial outer membrane, thereby impairing mitochondrial membrane potential, inducing mitochondrial leakage and promoting cell death. The phosphorylated form (mediated by ATM) plays a role in the DNA damage response and is involved in the ionizing radiation (IR)-induced S phase checkpoint control and in the recruitment of the MRN complex into the IR-induced foci (IRIF). Exhibits histone acetyltransferase (HAT) activity which specifically acetylates histones H2B and H4 in vitro. In concert with CUL3 and RBX1, promotes the degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. Can elicit oncogenic or tumor suppressor activities depending on the tissue or cell type.SUBUNIT Binds DNA as a dimer and can form a homodimer in the absence of DNA. Can form a heterodimer with JUN. Heterodimerization is essential for its transcriptional activity. Interacts with SMAD3 and SMAD4. Binds through its N-terminal region to UTF1 which acts as a coactivator of ATF2 transcriptional activity. Interacts with the HK1/VDAC1 complex. Interacts with NBN, MRE11, XPO1, KAT5 and CUL3.TISSUE SPECIFICITY Ubiquitously expressed, with more abundant expression in the brain.DOMAIN The nuclear export signal 1 (N-NES) negatively regulates its nuclear localization and transcriptional activity.PTM Phosphorylation of Thr-69 by MAPK14 and MAPK11, and at Thr-71 by MAPK1/ERK2, MAPK3/ERK1, MAPK11, MAPK12 and MAPK14 in response to external stimulus like insulin causes increased transcriptional activity. Phosphorylated by PLK3 following hyperosmotic stress. Also phosphorylated and activated by JNK and CaMK4. ATM-mediated phosphorylation at Ser-490 and Ser-498 stimulates its function in DNA damage response. Phosphorylation at Ser-62, Thr-73 and Ser-121 activates its transcriptional activity. Phosphorylation at Thr-69 or Thr-71 enhances its histone acetyltransferase (HAT) activity.SIMILARITY Belongs to the bZIP family. ATF subfamily.

UniProtP15336

EQUAL

505

EQUAL

Reactome DB_ID: 450243

O-phospho-L-threonine at 71

EQUAL

O-phospho-L-threonine at 69

EQUAL

505

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 450307

Activated MAPK kinases ERK1/2, JNK, p38 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T,Y-MAPK8 [nucleoplasm]p-T180,Y182-MAPK14 [nucleoplasm]p-T221,Y223-MAPK10 [nucleoplasm]p-T180,Y182-MAPK11 [nucleoplasm]p-T183,Y185-MAPK9 [nucleoplasm]

Reactome Database ID Release 70167971Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167971Reactome Database ID Release 70168053Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168053ReactomeR-HSA-168053

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168053.112110590Pubmed2002Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38Ouwens, DMde Ruiter, NDvan der Zon, GCCarter, APSchouten, Jvan der Burgt, CKooistra, KBos, JLMaassen, JAvan Dam, HEMBO J 21:3782-9319647037Pubmed2009The nuclear appearance of ERK1/2 and p38 determines the sequential induction of ATF2-Thr71 and ATF2-Thr69 phosphorylation by serum in JNK-deficient cellsBaan, Bvan der Zon, GCMaassen, JAOuwens, DMMol Cell Endocrinol 311:94-100

2.7.11

Activated JNKs phosphorylate c-JUN

JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus.

Authored: Luo, F, 2005-11-10 11:23:18Reviewed: Gay, NJ, 2006-04-24 16:48:17Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 29358

Reactome DB_ID: 450250

UniProt:P05412 JUN

JUN

JUNFUNCTION Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3' (PubMed:10995748, PubMed:22083952). Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation (PubMed:17210646). Involved in activated KRAS-mediated transcriptional activation of USP28 in colorectal cancer (CRC) cells (PubMed:24623306). Binds to the USP28 promoter in colorectal cancer (CRC) cells (PubMed:24623306).SUBUNIT Heterodimer with either FOS or BATF3 or ATF7 (PubMed:10376527, PubMed:12087103, PubMed:15467742). The ATF7/JUN heterodimer is essential for ATF7 transactivation activity (PubMed:10376527). Interacts with DSIPI; the interaction inhibits the binding of active AP1 to its target DNA (By similarity). Interacts with HIVEP3 and MYBBP1A (By similarity). Interacts with SP1, SPIB and TCF20 (PubMed:10196196, PubMed:16478997, PubMed:8663478). Interacts with COPS5; the interaction leads indirectly to its phosphorylation (PubMed:8837781). Component of the SMAD3/SMAD4/JUN/FOS/complex which forms at the AP1 promoter site (PubMed:10995748). The SMAD3/SMAD4 heterodimer acts synergistically with the JUN/FOS heterodimer to activate transcription in response to TGF-beta (PubMed:9732876). Interacts (via its basic DNA binding and leucine zipper domains) with SMAD3 (via an N-terminal domain); the interaction is required for TGF-beta-mediated transactivation of the SMAD3/SMAD4/JUN/FOS/complex (PubMed:10995748). Interacts with methylated RNF187 (PubMed:20852630, PubMed:23624934). Binds to HIPK3. Interacts (when phosphorylated) with FBXW7 (PubMed:14739463). Found in a complex with PRR7 and FBXW7 (PubMed:27458189). Interacts with PRR7 and FBXW7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (PubMed:27458189). Interacts with RBM39 (By similarity).PTM Ubiquitinated by the SCF(FBXW7), leading to its degradation (PubMed:14739463, PubMed:27458189). Ubiquitination takes place following phosphorylation, that promotes interaction with FBXW7 (PubMed:14739463).PTM Phosphorylated by CaMK4 and PRKDC; phosphorylation enhances the transcriptional activity. Phosphorylated by HIPK3. Phosphorylated by DYRK2 at Ser-243; this primes the protein for subsequent phosphorylation by GSK3B at Thr-239. Phosphorylated at Thr-239, Ser-243 and Ser-249 by GSK3B; phosphorylation reduces its ability to bind DNA. Phosphorylated by PAK2 at Thr-2, Thr-8, Thr-89, Thr-93 and Thr-286 thereby promoting JUN-mediated cell proliferation and transformation. Phosphorylated by PLK3 following hypoxia or UV irradiation, leading to increase DNA-binding activity.PTM Acetylated at Lys-271 by EP300.SIMILARITY Belongs to the bZIP family. Jun subfamily.

UniProtP05412

EQUAL

331

EQUAL

Reactome DB_ID: 113582

Reactome DB_ID: 450237

O-phospho-L-serine at 63

EQUAL

O-phospho-L-serine at 73

EQUAL

331

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 450253

GO0004705

GO molecular function

Reactome Database ID Release 70450228Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450228Reactome Database ID Release 70168136Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168136ReactomeR-HSA-168136

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168136.110871633Pubmed2000c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activityDennler, SPrunier, CFerrand, NGauthier, JMAtfi, AJ Biol Chem 275:28858-659561845Pubmed1998Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to developmentIp, YTDavis, RJCurr Opin Cell Biol 10:205-1918793328Pubmed2008c-Jun expression, activation and function in neural cell death, inflammation and repairRaivich, GJ Neurochem 107:898-906

2.7.11

c-FOS activation by phospho ERK1/2

The Fos proteins(c-Fos, FosB, Fra1 and Fra2), which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA binding activity. On activation of the MAPK pathway, Ser-374 of Fos is phosphorylated by ERK1/2 and Ser-362 is phosphorylated by RSK1/2, the latter kinases being activated by ERK1/2. If stimulation of the MAPK pathway is sufficiently sustained, ERK1/2 can dock on an upstream FTYP amino acid motif, called the DEF domain (docking site for ERKs, FXFP), and phosphorylate Thr-331 and Thr-325.Phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including Jun and Fos, without having any effect on their DNA binding activities. Thus, phosphorylation of Ser-362 and Ser-374 stabilizes c-Fos but has no demonstrated role in the control of transcriptional activity. On the contrary, phosphorylation of Thr-325 and Thr-331 enhances c-Fos transcriptional activity but has no demonstrated effect on protein turnover.

Authored: Shamovsky, V, 2009-12-16Reviewed: Gillespie, ME, 2010-02-27Edited: Shamovsky, V, 2010-02-27

Reactome DB_ID: 450216

UniProt:P01100 FOS

FOS

FOSG0S7FUNCTION Nuclear phosphoprotein which forms a tight but non-covalently linked complex with the JUN/AP-1 transcription factor. In the heterodimer, FOS and JUN/AP-1 basic regions each seems to interact with symmetrical DNA half sites. On TGF-beta activation, forms a multimeric SMAD3/SMAD4/JUN/FOS complex at the AP1/SMAD-binding site to regulate TGF-beta-mediated signaling. Has a critical function in regulating the development of cells destined to form and maintain the skeleton. It is thought to have an important role in signal transduction, cell proliferation and differentiation. In growing cells, activates phospholipid synthesis, possibly by activating CDS1 and PI4K2A. This activity requires Tyr-dephosphorylation and association with the endoplasmic reticulum.SUBUNIT Heterodimer; with JUN (By similarity). Interacts with MAFB (By similarity). Component of the SMAD3/SMAD4/JUN/FOS complex required for synergistic TGF-beta-mediated transcription at the AP1 promoter site. Interacts with SMAD3; the interaction is weak even on TGF-beta activation. Interacts with MAFB. Interacts with DSIPI; this interaction inhibits the binding of active AP1 to its target DNA. Interacts with CDS1 and PI4K2A (By similarity).DEVELOPMENTAL STAGE Expressed at very low levels in quiescent cells. When cells are stimulated to reenter growth, they undergo 2 waves of expression, the first one peaks 7.5 minutes following FBS induction. At this stage, the protein is localized endoplasmic reticulum. The second wave of expression occurs at about 20 minutes after induction and peaks at 1 hour. At this stage, the protein becomes nuclear.PTM Phosphorylated in the C-terminal upon stimulation by nerve growth factor (NGF) and epidermal growth factor (EGF). Phosphorylated, in vitro, by MAPK and RSK1. Phosphorylation on both Ser-362 and Ser-374 by MAPK1/2 and RSK1/2 leads to protein stabilization with phosphorylation on Ser-374 being the major site for protein stabilization on NGF stimulation. Phosphorylation on Ser-362 and Ser-374 primes further phosphorylations on Thr-325 and Thr-331 through promoting docking of MAPK to the DEF domain. Phosphorylation on Thr-232, induced by HA-RAS, activates the transcriptional activity and antagonizes sumoylation. Phosphorylation on Ser-362 by RSK2 in osteoblasts contributes to osteoblast transformation (By similarity).PTM Constitutively sumoylated with SUMO1, SUMO2 and SUMO3. Desumoylated by SENP2. Sumoylation requires heterodimerization with JUN and is enhanced by mitogen stimulation. Sumoylation inhibits the AP-1 transcriptional activity and is, itself, inhibited by Ras-activated phosphorylation on Thr-232.PTM In quiescent cells, the small amount of FOS present is phosphorylated at Tyr-10 and Tyr-30 by SRC. This Tyr-phosphorylated form is cytosolic. In growing cells, dephosphorylated by PTPN2. Dephosphorylation leads to the association with endoplasmic reticulum membranes and activation of phospholipid synthesis.SIMILARITY Belongs to the bZIP family. Fos subfamily.

UniProtP01100

EQUAL

380

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 113582

Reactome DB_ID: 450283

O-phospho-L-serine at 362

362

EQUAL

O-phospho-L-serine at 374

374

EQUAL

O-phospho-L-threonine at 325

325

EQUAL

O-phospho-L-threonine at 331

331

EQUAL

380

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 198701

Reactome Database ID Release 70450325Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450325ReactomeR-HSA-450325

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450325.17588633Pubmed1995The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cellsOkazaki, KSagata, NEMBO J 14:5048-5912134156Pubmed2002Molecular interpretation of ERK signal duration by immediate early gene productsMurphy, LOSmith, StuartChen, RHFingar, DCBlenis, JNat Cell Biol 4:556-64

Formation of Activated Protein 1 (AP-1) complex. ATF2/c-JUN heterodimer.

At the beginning of this reaction, 1 molecule of 'c-Jun-P', and 1 molecule of 'ATF-2-P' are present. At the end of this reaction, 1 molecule of 'AP-1' is present.

Authored: Luo, F, 2005-11-16 12:05:41Reviewed: Gay, NJ, 2006-04-24 16:48:17Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 450243

O-phospho-L-threonine at 71

EQUAL

O-phospho-L-threonine at 69

EQUAL

505

EQUAL

Reactome DB_ID: 450237

O-phospho-L-serine at 63

EQUAL

O-phospho-L-serine at 73

EQUAL

331

EQUAL

Reactome DB_ID: 450262

p-2S-cJUN:p-2T-ATF2 [nucleoplasm]

p-2S-cJUN:p-2T-ATF2

AP-1 heterodimer phosphorylated

Reactome DB_ID: 450243

O-phospho-L-threonine at 71

EQUAL

O-phospho-L-threonine at 69

EQUAL

505

EQUAL

Reactome DB_ID: 450237

O-phospho-L-serine at 63

EQUAL

O-phospho-L-serine at 73

EQUAL

331

EQUAL

Reactome Database ID Release 70450262Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450262ReactomeR-HSA-450262

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450262.1Reactome Database ID Release 70168440Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168440ReactomeR-HSA-168440

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168440.19030721Pubmed1997Regulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione-S-transferase gene expression by chemical agentsAinbinder, EBergelson, SPinkus, RDaniel, VEur J Biochem 243:49-57

Formation of Activated Protein 1 (AP-1) complex. cFOS/c-JUN heterodimer.

The bZIP domains of Jun and Fos form an X-shaped -helical structure, which binds to the palindromic AP-1 site (TGAGTCA) (Glover and Harrison, 1995).

Authored: Luo, F, 2005-11-16 12:05:41Reviewed: Gay, NJ, 2006-04-24 16:48:17Edited: Shamovsky, V, 2009-12-16

Reactome DB_ID: 450237

O-phospho-L-serine at 63

EQUAL

O-phospho-L-serine at 73

EQUAL

331

EQUAL

Reactome DB_ID: 450283

O-phospho-L-serine at 362

362

EQUAL

O-phospho-L-serine at 374

374

EQUAL

O-phospho-L-threonine at 325

325

EQUAL

O-phospho-L-threonine at 331

331

EQUAL

380

EQUAL

Reactome DB_ID: 450327

p-2S-cJUN:p-2S,2T-cFOS [nucleoplasm]

p-2S-cJUN:p-2S,2T-cFOS

AP-1(cJun:cFos) phosphorylated