BioPAX pathway converted from "Toll Like Receptor 2 (TLR2) Cascade" in the Reactome database.

Toll Like Receptor 2 (TLR2) Cascade

This event has been computationally inferred from an event that has been demonstrated in another species.The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>

Toll Like Receptor TLR1:TLR2 Cascade

MyD88:MAL(TIRAP) cascade initiated on plasma membrane

IRAK2 mediated activation of TAK1 complex

IRAK2 induces TRAF6 oligomerization

Reactome DB_ID: 10515883

cytosolGO0005829

UniProt:Q9W3I9Traf6

Reactomehttp://www.reactome.orgDrosophila melanogaster

NCBI Taxonomy7227UniProtQ9W3I9

Chain Coordinates

EQUAL

522

EQUAL

Reactome DB_ID: 10520603

plasma membraneGO0005886TRAF6:p-IRAK2 [plasma membrane]

TRAF6:p-IRAK2

Reactome DB_ID: 10520599

EQUAL

522

EQUAL

Reactome DB_ID: 10520601

UniProt:Q05652 pll

pll

pllCG5974FUNCTION Plays an essential role in the Tl receptor signaling pathway that establishes embryonic dorsoventral polarity; the signal directs import of dl into ventral and ventrolateral nuclei, thereby establishing dorsoventral polarity. Tub recruits pll to the plasma membrane and protein-protein interaction activates pll.SUBUNIT Interacts (via Death domain) with tub (via Death domain). Interacts with Pellino (Pli).DEVELOPMENTAL STAGE Expressed both maternally and zygotically with low levels of expression throughout the life cycle.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.

UniProtQ05652

phosphorylated residue at unknown position

phosphorylated residue [MOD:00696]

EQUAL

625

EQUAL

Reactome Database ID Release 7510520603Database 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=10520603ReactomeR-DME-936961

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-DME-936961.1

Reactome DB_ID: 10520605

p-IRAK2:oligo-TRAF6 [plasma membrane]

p-IRAK2:oligo-TRAF6

Reactome DB_ID: 10520599

EQUAL

522

EQUAL

Reactome DB_ID: 10520603

Reactome Database ID Release 7510520605Database 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=10520605ReactomeR-DME-936990

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-DME-936990.1Reactome Database ID Release 7510520615Database 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=10520615ReactomeR-DME-936963

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-DME-936963.1The mechanism by which IRAK-2 induces TRAF6 E3 ligase activity remains to be deciphered, but one possibility is that IRAK-2 may direct TRAF6 oligomerization.

17878161Pubmed2007IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitinationKeating, SEMaloney, GMMoran, EMBowie, AGJ Biol Chem 282:33435-43inferred by electronic annotationIEAGOIEA

6.3.2.19

Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2

Converted from EntitySet in Reactome

Reactome DB_ID: 10491404

Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBI-P63E 3 [cytosol]UBI-P63E 12 [cytosol]Ubi-p5E [cytosol]UBI-P63E 1 [cytosol]UBI-P63E 2 [cytosol]

UniProtP0CG69UniProtP18101UniProtQ9W418

Reactome DB_ID: 10520605

Reactome DB_ID: 10520610

p-IRAK2:K63-linked pUb oligo-TRAF6 [plasma membrane]

p-IRAK2:K63-linked pUb oligo-TRAF6

Reactome DB_ID: 10520608

ubiquitinylated lysine (K63polyUb [plasma membrane]) at 124 (in Homo sapiens)

124

EQUAL

ubiquitinylated lysine [MOD:01148]

EQUAL

522

EQUAL

Reactome DB_ID: 10520601

phosphorylated residue at unknown position

EQUAL

625

EQUAL

Reactome Database ID Release 7510520610Database 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=10520610ReactomeR-DME-936988

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-DME-936988.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10520605

GO0004842

GO molecular function

Reactome Database ID Release 7510520611Database 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=10520611Reactome Database ID Release 7510520613Database 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=10520613ReactomeR-DME-936942

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-DME-936942.1TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. 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.

17135271Pubmed2007Site-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 282:4102-12inferred by electronic annotationIEAGOIEA

6.3.2.19

Activated TRAF6 synthesizes unanchored polyubiquitin chains

Converted from EntitySet in Reactome

Reactome DB_ID: 10491404

Reactome DB_ID: 10502069

K63polyUb [cytosol]

K63polyUb

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10520610

Reactome Database ID Release 7510520616Database 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=10520616Reactome Database ID Release 7510520618Database 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=10520618ReactomeR-DME-936986

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-DME-936986.1Polyubiquitinated TRAF6 (as E3 ubiquitin ligase) 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.

19675569Pubmed2009Direct activation of protein kinases by unanchored polyubiquitin chainsXia, ZPSun, LChen, XPineda, GJiang, XAdhikari, AZeng, WChen, ZJNatureinferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510568847Database 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=10568847ReactomeR-DME-937042

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-DME-937042.1Although IRAK-1 was originally thought to be a key mediator of TRAF6 activation in the IL1R/TLR signaling (Dong W et al. 2006), recent studies showed that IRAK-2, but not IRAK-1, led to TRAF6 polyubiquitination (Keating SE et al 2007). IRAK-2 loss-of-function mutants, with mutated TRAF6-binding motifs, could no longer activate NF-kB and could no longer stimulate TRAF-6 ubiquitination (Keating SE et al 2007). Furthermore, the proxyvirus protein A52 - an inhibitor of all IL-1R/TLR pathways to NF-kB activation, was found to interact with both IRAK-2 and TRAF6, but not IRAK-1. Further work showed that A52 inhibits IRAK-2 functions, whereas association with TRAF6 results in A52-induced MAPK activation. The strong inhibition effect of A52 was also observed on the TLR3-NFkB axis and this observation led to the discovery that IRAK-2 is recruited to TLR3 to activate NF-kB (Keating SE et al 2007). Thus, A52 possibly inhibits MyD88-independent TLR3 pathways to NF-kB via targeting IRAK-2 as it does for other IL-1R/TLR pathways, although it remains unclear how IRAK-2 is involved in TLR3 signaling.IRAK-2 was shown to have two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002).

21606490Pubmed2011Human interleukin-1 receptor-associated kinase-2 is essential for Toll-like receptor-mediated transcriptional and post-transcriptional regulation of tumor necrosis factor alphaFlannery, Sinead MKeating, Sinead ESzymak, JoannaBowie, Andrew GJ. Biol. Chem. 286:23688-9712140561Pubmed2002Distinct molecular mechanism for initiating TRAF6 signallingYe, HArron, JRLamothe, BCirilli, MKobayashi, TShevde, NKSegal, DDzivenu, OKVologodskaia, MYim, MDu, KSingh, SPike, JWDarnay, BGChoi, YWu, HNature 418:443-716831874Pubmed2006The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4Dong, WLiu, YPeng, JChen, LZou, TXiao, HLiu, ZLi, WBu, YQi, YJ Biol Chem 281:26029-40inferred by electronic annotationIEAGOIEA

IRAK1 recruits IKK complex

Pellino binds hp-IRAK1:TRAF6

Reactome DB_ID: 10520624

TRAF6:hp-IRAK1 [plasma membrane]

TRAF6:hp-IRAK1

Reactome DB_ID: 10520599

EQUAL

522

EQUAL

Reactome DB_ID: 10520622

O-phospho-L-threonine at 387 (in Homo sapiens)

387

EQUAL

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

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

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

O-phospho-L-threonine at 209 (in Homo sapiens)

209

EQUAL

O-phospho-L-serine at unknown position

O-phospho-L-threonine at unknown position

EQUAL

712

EQUAL

Reactome Database ID Release 7510520624Database 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=10520624ReactomeR-DME-937036

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-DME-937036.1

Reactome DB_ID: 10516501

UniProt:O77237Pli

UniProtO77237

phosphorylated residue at unknown position

EQUAL

418

EQUAL

Reactome DB_ID: 10520626

TRAF6:hp-IRAK1:Pellino [plasma membrane]

TRAF6:hp-IRAK1:Pellino

Reactome DB_ID: 10520624

Reactome DB_ID: 10516501

phosphorylated residue at unknown position

EQUAL

418

EQUAL

Reactome Database ID Release 7510520626Database 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=10520626ReactomeR-DME-937020

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-DME-937020.1Reactome Database ID Release 7510520631Database 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=10520631ReactomeR-DME-937044

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-DME-937044.1Pellino isoforms -1, 2 and 3 have been shown to interact with IRAK1 and IRAK4 (Jiang et al. 2003, Strellow et al. 2003, Butler et al. 2005, 2007). It has been also reported that Pellino-1 forms a complex with TRAF6, but not TAK1 or IL1R (Jiang et al. 2003), suggesting that Pellino-1 function as intermediate complex with IRAK1 in the propagation of signal from the activated receptor to activation of TAK1. All Pellino isoforms function as E3 ubiquitin ligases in conjunction with several different E2-conjugating enzymes - Ubc13-Uev1a, UbcH4, or UbcH5a/5b.(Schauvliege R et al. 2006, Butler MP et al. 2007, Ordureau A et al. 2008). Their C-terminus contains a RING-like domain which is responsible for IL1-induced Lys63-linked polyubiquitination of IRAK1 in vitro.

12496252Pubmed2003Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complexJiang, ZJohnson, HJNie, HQin, JBird, TALi, XJ Biol Chem 278:10952-615917247Pubmed2005Pellino3 is a novel upstream regulator of p38 MAPK and activates CREB in a p38-dependent mannerButler, MPHanly, JAMoynagh, PNJ Biol Chem 280:27759-6817997719Pubmed2008The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1Ordureau, ASmith, HWindheim, MPeggie, MCarrick, EMorrice, NCohen, PBiochem J 409:43-5218326498Pubmed2008Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activationXiao, HQian, WStaschke, KQian, YCui, GDeng, LEhsani, MWang, XQian, YWChen, ZJGilmour, RJiang, ZLi, XJ Biol Chem 283:14654-6416884718Pubmed2006Pellino proteins are more than scaffold proteins in TLR/IL-1R signalling: a role as novel RING E3-ubiquitin-ligasesSchauvliege, RJanssens, SBeyaert, RFEBS Lett 580:4697-70212860405Pubmed2003Characterization of Pellino2, a substrate of IRAK1 and IRAK4Strelow, AKollewe, CWesche, HFEBS Lett 547:157-6119022706Pubmed2009The Pellino family: IRAK E3 ligases with emerging roles in innate immune signallingMoynagh, PNTrends Immunol 30:33-4217675297Pubmed2007Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligasesButler, MPHanly, JAMoynagh, PNJ Biol Chem 282:29729-37inferred by electronic annotationIEAGOIEA

IRAK1 phosphorylates Pellino

Reactome DB_ID: 10520626

Reactome DB_ID: 113592

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 10520626

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

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

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10520626

GO0004672

GO molecular function

Reactome Database ID Release 7510520627Database 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=10520627Reactome Database ID Release 7510520629Database 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=10520629ReactomeR-DME-937034

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-DME-937034.1Both IRAK1 and IRAK4 were shown to phosphorylate Pellino isoforms in vitro. The phosphorylation of Pellino proteins is a necessary step in enhancing of their E3 ubiquitin ligase activity. It remains unclear whether IRAK1(as shown here), IRAK4, or both protein kinases mediate the activation of Pellino isoforms in vivo.

19264966Pubmed2009Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4Smith, HPeggie, MCampbell, DGVandermoere, FCarrick, ECohen, PProc Natl Acad Sci U S A 106:4584-90inferred by electronic annotationIEAGOIEA

Pellino ubiquitinates hp-IRAK1

Reactome DB_ID: 10502069

Reactome DB_ID: 10520626

Reactome DB_ID: 10506827

UBE2N:UBE2V1 [cytosol]

UBE2N:UBE2V1

Reactome DB_ID: 10506821

UniProt:P35128 ben

ben

CG18319benUbcD3FUNCTION Catalyzes the covalent attachment of ubiquitin to other proteins.PATHWAY Protein modification; protein ubiquitination.DISRUPTION PHENOTYPE Mutants in this gene exhibit several, largely neuronal defects including lesions affecting the neuronal connectivity of the giant fiber with the 'jumping muscle', and the axons of photoreceptor cells R7 and R8 fail to make the proper right-angle turn into the medulla (hence the term 'bendless').SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.

UniProtP35128

EQUAL

152

EQUAL

Reactome DB_ID: 10506825

UniProt:Q9VRL1 Uev1A

Uev1A

Dmel_CG10640Uev1ACG10640SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.

UniProtQ9VRL1

EQUAL

147

EQUAL

Reactome Database ID Release 7510506827Database 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=10506827ReactomeR-DME-202463

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-DME-202463.1

Reactome DB_ID: 10506827

Reactome DB_ID: 10520620

K63-linked polyUb p-IRAK1:TRAF6 [cytosol]

K63-linked polyUb p-IRAK1:TRAF6

Reactome DB_ID: 10515883

EQUAL

522

EQUAL

Reactome DB_ID: 10516696

O-phospho-L-threonine at 209 (in Homo sapiens)

209

EQUAL

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

O-phospho-L-threonine at 387 (in Homo sapiens)

387

EQUAL

O-phospho-L-threonine at unknown position

O-phospho-L-serine at unknown position

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 134 (in Homo sapiens)

134

EQUAL

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 160 (in Homo sapiens)

160

EQUAL

712

EQUAL

Reactome Database ID Release 7510520620Database 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=10520620ReactomeR-DME-937043

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-DME-937043.1

Reactome DB_ID: 10516501

phosphorylated residue at unknown position

EQUAL

418

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10520626

GO0034450

GO molecular function

Reactome Database ID Release 7510520632Database 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=10520632Reactome Database ID Release 7510520634Database 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=10520634ReactomeR-DME-937050

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-DME-937050.1IL1R/TLR induces the Lys48- polyubiquitination and proteosomal degradation of IRAK1. IRAK1 has been shown to undergo Lys63-linked polyubiquitination which induced activation of NFkB (Windheim et al 2008; Conze et al 2008). These two forms of ubiquitination are not mutually exclusive for a protein (Newton K et al 2008). Upon stimulation Lys63-linked ubiquitination may occur first to activate NFkB, but at later time Lys48-linked ubiquitination occurs to target the proteins for proteosomal degradation.IRAK1 is ubiquitinated on Lys134 and Lys180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is a stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al 2008; Butler et al 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and Lys48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13/Uev1a to catalyze Lys63-linked ubiquitylation (Ordureau et al 2008).

18347055Pubmed2008Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activationConze, DBWu, CJThomas, JALandstrom, AAshwell, JDMol Cell Biol 28:3538-4718180283Pubmed2008Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinaseWindheim, MStafford, MPeggie, MCohen, PMol Cell Biol 28:1783-9118724939Pubmed2008Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodiesNewton, KimMatsumoto, Marissa LWertz, Ingrid EKirkpatrick, Donald SLill, Jennie RTan, JenilleDugger, DebraGordon, NathanielSidhu, SSFellouse, FAKomuves, LaszloFrench, Dorothy MFerrando, Ronald ELam, CynthiaCompaan, DeanneYu, ChristineBosanac, IvanHymowitz, Sarah GKelley, Robert FDixit, Vishva MCell 134:668-78inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510568849Database 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=10568849ReactomeR-DME-937039

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-DME-937039.1GO0043123

GO biological process

The role of IRAK1 kinase activity in the activation of NF-kappa-B by IL-1/TLR is still uncertain. It has been shown that a kinase-dead IRAK1 mutants can still activate NF-kappa-B. Furthermore, stimulation of IRAK1-deficient I1A 293 cells with LMP1 (latent membrane protein 1- a known viral activator of NF-kappa-B) leads to TRAF6 polyubiquitination and IKKbeta activation [Song et al 2006]. On the other hand, IRAK1 enhances p65 Ser536 phosphorylation [Song et al 2006] and p65 binding to the promoter of NF-kappa-B dependent target genes [Liu G et al 2008]. IRAK1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK1 prevented interaction with the NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NF-kappa-B activation [Conze et al 2008]. These data suggest that kinase activity of IRAK1 is not essential for its ability to activate NF-kappa-B, while its Lys63-polyubuquitination allows IRAK1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NF-kappa-B. Upon IL-1/TLR stimulation IRAK1 protein can undergo covalent modifications including phosphorylation [Kollewe et al 2004], ubiquitination [Conze DB et al 2008] and sumoylation [Huang et al 2004]. Depending upon the nature of its modification, IRAK1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NF-kappa-B [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003].

14625308Pubmed2004Sequential autophosphorylation steps in the interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 SignalingKollewe, CMackensen, ACNeumann, DKnop, JCao, PLi, SWesche, HMartin, MUJ Biol Chem 279:5227-3618276832Pubmed2008Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-kappaB activation requires cytosolic and nuclear activityLiu, GPark, YJAbraham, EFASEB J 22:2285-9616477006Pubmed2006IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-kappaB activationSong, YJJen, KYSoni, VKieff, ECahir-McFarland, EProc Natl Acad Sci U S A 103:2689-9415695821Pubmed2005The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signalingSchoenemeyer, ABarnes, BJMancl, MELatz, EGoutagny, NPitha-Rowe, Paula MFitzgerald, Katherine AGolenbock, DTJ Biol Chem 280:17005-1212856330Pubmed2003IRAK-dependent phosphorylation of Stat1 on serine 727 in response to interleukin-1 and effects on gene expressionNguyen, HChatterjee-Kishore, MJiang, ZQing, YRamana, CVBayes, JCommane, MLi, XStark, GRJ Interferon Cytokine Res 23:183-9214661019Pubmed2004Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3Huang, QYang, JLin, YWalker, Graham CCheng, JLiu, ZGSu, BNat Immunol 5:98-10315767370Pubmed2005Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} inductionUematsu, SSato, SYamamoto, MHirotani, TKato, HTakeshita, FMatsuda, MCoban, CIshii, KJKawai, TTakeuchi, OAkira, ShizuoJ Exp Med 201:915-23inferred by electronic annotationIEAGOIEA

TAK1 activates NFkB by phosphorylation and activation of IKKs complex

NFkB inhibitor binds NFkB complex

Reactome DB_ID: 10501976

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

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

Converted from EntitySet in Reactome

Reactome DB_ID: 10501968

Homologues of RELA [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDif [cytosol]dl [cytosol]

UniProtP98149UniProtP15330

Reactome DB_ID: 10501972

UniProt:Q94527 Rel

Rel

RelCG11992FUNCTION Plays a key role in the humoral immune response (PubMed:8816802, PubMed:10619029, PubMed:11269501, PubMed:11872802, PubMed:22022271). Rel-p68 subunit translocates to the nucleus where it binds to the promoter of the Cecropin A1 gene and probably other antimicrobial peptide genes (PubMed:11269501). I-kappa-B kinase complex (IKKbeta and key) and PGRP-LC are essential signaling components in transmitting the lipopolysaccharide (LPS) signal leading to cact degradation for NF-kappa-B (rel) activation (PubMed:11872802, PubMed:11018014). Part of a Toll-related receptor pathway that functions in the apoptosis of unfit cells during cell competition (PubMed:25477468). May be part of a NF-kappa-B and Tollo signaling cascade that regulates development of the peripheral nervous system (PubMed:18000549). Possibly post-transcriptionally regulates the neuron-specific genes sc and ase, by promoting the rapid turnover of their transcripts in the wing imaginal disk (PubMed:18000549).SUBUNIT Rel-p68 subunit interacts with Dredd (PubMed:11269502). Interacts with DMAP1 (PubMed:24947515). Interacts with akirin; interaction is immune stimulation-dependent; activates selected rel target gene promoters (PubMed:25180232).DEVELOPMENTAL STAGE Expressed both maternally and zygotically.INDUCTION By bacteria and fungi.PTM Phosphorylated by lipopolysaccharide (LPS)-activated I-kappa-B kinase complex before being cleaved. Rel-p110 subunit is cleaved within seconds of an immune challenge into Rel-p49 subunit and Rel-p68 subunit. Rel-p110 subunit reappears after 45 minutes.DISRUPTION PHENOTYPE Larvae infected with Gram-negative bacteria fail to activate tracheal expression of the antibacterial peptide gene Drs (PubMed:22022271). Ectopic bristles develop on the dorsocentral, scutellar and lateral regions of the noctum, with one or more ectopic bristles per hemi-notum (PubMed:18000549).

UniProtQ94527

EQUAL

433

EQUAL

Reactome Database ID Release 7510501976Database 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=10501976ReactomeR-DME-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-DME-168155.1

Reactome DB_ID: 10501980

UniProt:Q03017 cact

cact

cactCG5848FUNCTION Involved in the formation of the dorsoventral pattern. It inhibits nuclear translocation of the dorsal morphogen in the dorsal region of the embryo. Acts as a negative regulator of the NF-kappa-B (rel) signaling pathway. Cact is degraded by IKKbeta, this is essential for NF-kappa-B (rel) activation.SUBUNIT Phosphorylated isoform A binds to dorsal (dl); inhibits dl translocation to the nucleus and therefore from binding to DNA. In vitro, interacts with IKKbeta. Interacts with cactin and kappa-B-Ras.TISSUE SPECIFICITY Expressed in ovary (at protein level).DEVELOPMENTAL STAGE Expressed during embryogenesis (at protein level). Isoform A is expressed in ovaries and 0-1 hour embryos. After 2-3 hours unphosphorylated zygotic protein is expressed. Between 4-8 hours phosphorylated zygotic protein is expressed. After 12 hours the amount of unphosphorylated zygotic protein increases until, by the end of embryogenesis, it is the most abundant form of cactus.PTM Activated IKKbeta phosphorylates cact.SIMILARITY Belongs to the NF-kappa-B inhibitor family.

UniProtQ03017

EQUAL

317

EQUAL

Reactome DB_ID: 10501982

NFkB inhibitor:NFkB complex [cytosol]

NFkB inhibitor:NFkB complex

Reactome DB_ID: 10501976

Reactome DB_ID: 10501980

EQUAL

317

EQUAL

Reactome Database ID Release 7510501982Database 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=10501982ReactomeR-DME-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-DME-168130.1Reactome Database ID Release 7510566233Database 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=10566233ReactomeR-DME-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-DME-9630923.1NFkB 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).

15145317Pubmed2004The two NF-kappaB activation pathways and their role in innate and adaptive immunityBonizzi, GKarin, MTrends Immunol 25:280-810837071Pubmed2000Phosphorylation meets ubiquitination: the control of NF-[kappa]B activityKarin, MBen-Neriah, YAnnu. Rev. Immunol. 18:621-6322435548Pubmed2012Regulation of NF-κB by ubiquitination and degradation of the IκBsKanarek, NaamaBen-Neriah, YinonImmunol. Rev. 246:77-9422435546Pubmed2012NF-κB regulation: lessons from structuresGhosh, GourisankarWang, Vivien Ya-FanHuang, De-BinFusco, AmandaImmunol. Rev. 246:36-5821203422Pubmed2010Structure-function relationship of cytoplasmic and nuclear IκB proteins: an in silico analysisManavalan, BalachandranBasith, ShaherinChoi, Yong-MinLee, GwangChoi, SangdunPLoS ONE 5:e157829865693Pubmed1998Structure of an IkappaBalpha/NF-kappaB complexJacobs, M DHarrison, S CCell 95:749-5821094161Pubmed2011The RelA nuclear localization signal folds upon binding to IκBαCervantes, Carla FBergqvist, SimonKjaergaard, MagnusKroon, GerardSue, Shih-CheDyson, H JaneKomives, Elizabeth AJ. Mol. Biol. 405:754-6417072323Pubmed2006Transcriptional regulation via the NF-kappaB signaling moduleHoffmann, ANatoli, GGhosh, GOncogene 25:6706-16inferred by electronic annotationIEAGOIEA

NFkB complex is transported from cytosol to nucleus

Reactome DB_ID: 10501976

Reactome DB_ID: 10502020

nucleoplasmGO0005654NFkB Complex [nucleoplasm]

NFkB Complex

Converted from EntitySet in Reactome

Reactome DB_ID: 10502018

Homologues of RELA [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDif [nucleoplasm]dl [nucleoplasm]

Reactome DB_ID: 10502010

EQUAL

433

EQUAL

Reactome Database ID Release 7510502020Database 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=10502020ReactomeR-DME-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-DME-177673.1Reactome Database ID Release 7510502022Database 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=10502022ReactomeR-DME-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-DME-168166.1NFkB 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.

16056267Pubmed2005Ubiquitin signalling in the NF-kappaB pathwayChen, ZJNat Cell Biol 7:758-6510723127Pubmed2000Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complexGil, JAlcami, JEsteban, MOncogene 19:1369-78inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510567955Database 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=10567955ReactomeR-DME-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-DME-445989.1GO0051092

GO biological process

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.

15837794Pubmed2005Simultaneous 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 280:27728-4111460167Pubmed2001TAK1 is a ubiquitin-dependent kinase of MKK and IKKWang, CDeng, LHong, MAkkaraju, GRInoue, JChen, ZJNature 412:346-51inferred by electronic annotationIEAGOIEA

MAP kinase activation

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

2.7.11.25

Activated TAK1 phosphorylates MKK4/MKK7

Reactome DB_ID: 10516169

UniProt:O61444Mkk4

UniProtO61444

EQUAL

399

EQUAL

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 10502005

O-phospho-L-serine at 257 (in Homo sapiens)

257

EQUAL

O-phospho-L-threonine at 261 (in Homo sapiens)

261

EQUAL

399

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10516177

p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex [cytosol]

p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex

Reactome DB_ID: 10502069

Reactome DB_ID: 10516175

p-IRAK2:K63-linked pUb oligo-TRAF6 [cytosol]

p-IRAK2:K63-linked pUb oligo-TRAF6

Reactome DB_ID: 10515894

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

124

EQUAL

522

EQUAL

Reactome DB_ID: 10516173

phosphorylated residue at unknown position

EQUAL

625

EQUAL

Reactome Database ID Release 7510516175Database 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=10516175ReactomeR-DME-937064

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-DME-937064.1

Reactome DB_ID: 10516171

Ghost homologue of p-T184,T187-MAP3K7 [cytosol]

Ghost homologue of p-T184,T187-MAP3K7

Reactome Database ID Release 7510516177Database 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=10516177ReactomeR-DME-937060

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-DME-937060.1GO0004709

GO molecular function

Reactome Database ID Release 7510516178Database 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=10516178Reactome Database ID Release 7510516180Database 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=10516180ReactomeR-DME-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-DME-450337.1In 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.

8533096Pubmed1995Identification 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 27:7935-4616186825Pubmed2005Essential function for the kinase TAK1 in innate and adaptive immune responsesSato, SSanjo, HTakeda, KNinomiya-Tsuji, JYamamoto, MKawai, TMatsumoto, KTakeuchi, OAkira, ShizuoNat Immunol 6:1087-95inferred by electronic annotationIEAGOIEA

2.7.11

Phosphorylation of human JNKs by activated MKK4/MKK7

Reactome DB_ID: 10501988

UniProt:P92208 bsk

bsk

JNKbskCG5680FUNCTION Responds to activation by environmental stress by phosphorylating a number of transcription factors, primarily components of AP-1 such as Jra and also the transcriptional repressor aop, and thus regulates transcriptional activity (PubMed:9224720). Component of the immune response activated by bacterial infection, and is involved in wound healing and in dorsal closure, a morphogenetic movement during embryogenesis (PubMed:8946915, PubMed:9224720, PubMed:10433922, PubMed:11784101). Functions in the systematic response to wounding acting downstream of the Hayan-phenoloxidase PPO1 cascade (PubMed:22227521). Exhibits cytoprotective activity in neuronal cells in response to wounding to the integument (PubMed:22227521). Controls the expression of a phosphatase, puckered, at the edges of wounded epidermal tissue and in the dorsal epithelium during dorsal closure (PubMed:10433922, PubMed:11784101). Regulates the activity of SREBP in neurons and thereby the accumulation of lipids in glia (PubMed:25594180).ACTIVITY REGULATION Activated by threonine and tyrosine phosphorylation by the dual specificity kinase, hep. Inhibited by dual specificity phosphatase, puckered.SUBUNIT Interacts with MKP-4 (via tyrosine-protein phosphatase domain); the interaction dephosphorylates bsk.TISSUE SPECIFICITY During gastrulation, expression is seen in cells undergoing morphogenetic movements. By stage 9 of embryonic development, expression is ubiquitous. At stages 12-14, expression occurs in epidermis and central nervous system. At stage 15, expression is restricted to ventral nerve cord, brain and some peripheral neurons. In larvae, expression is seen in all imaginal disks, with highest levels in wing and eye disks, and in the CNS. Adults express the protein in fat body and hemocytes.DEVELOPMENTAL STAGE Expressed maternally and zygotically through to adult (male and female).INDUCTION In neuronal cells by wounding of the integument (at protein level) (PubMed:22227521). Activated by increased levels of reactive oxygen species (ROS) (PubMed:25594180).DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-181 and Tyr-183, which activates the enzyme.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.

UniProtP92208

EQUAL

427

EQUAL

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 10501994

O-phospho-L-threonine at unknown position

O4'-phospho-L-tyrosine at unknown position

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

EQUAL

427

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10502005

O-phospho-L-serine at 257 (in Homo sapiens)

257

EQUAL

O-phospho-L-threonine at 261 (in Homo sapiens)

261

EQUAL

399

EQUAL

GO0008545

GO molecular function

Reactome Database ID Release 7510502006Database 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=10502006Reactome Database ID Release 7510502008Database 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=10502008ReactomeR-DME-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-DME-168162.1Activated 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).

18713996Pubmed2008Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinasesYoshizawa, THammaker, DSweeney, SEBoyle, DLFirestein, GSJ Immunol 181:3252-813130464Pubmed2003Expression 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 48:2450-6011062067Pubmed2000Synergistic 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 272:14489-96inferred by electronic annotationIEAGOIEA

Activated human JNKs migrate to nucleoplasm

Reactome DB_ID: 10501994

O-phospho-L-threonine at unknown position

O4'-phospho-L-tyrosine at unknown position

EQUAL

427

EQUAL

Reactome DB_ID: 10501930

O-phospho-L-threonine at unknown position

O4'-phospho-L-tyrosine at unknown position

EQUAL

427

EQUAL

Reactome Database ID Release 7510516188Database 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=10516188ReactomeR-DME-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-DME-450348.1c-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.

12193592Pubmed2002Evidence 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 272:16657-62inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510567949Database 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=10567949ReactomeR-DME-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-DME-450321.1GO0007254

GO biological process

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).

26988982Pubmed2016IL-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 14:7716937364Pubmed2006The 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 282:2092-58177321Pubmed1994The stress-activated protein kinase subfamily of c-Jun kinasesKyriakis, JMBanerjee, PNikolakaki, EDai, TRubie, EAAhmad, MFAvruch, JosephWoodgett, JRNature 369:156-60inferred by electronic annotationIEAGOIEA

activated TAK1 mediates p38 MAPK activation

2.7.11.25

activated human TAK1 phosphorylates MKK3/MKK6

Reactome DB_ID: 10516182

UniProt:O62602lic

UniProtO62602

EQUAL

347

EQUAL

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 10516144

O-phospho-L-serine at 189 (in Homo sapiens)

189

EQUAL

O-phospho-L-threonine at 193 (in Homo sapiens)

193

EQUAL

347

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10516177

Reactome Database ID Release 7510516186Database 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=10516186ReactomeR-DME-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-DME-450346.1Human 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 .

8622669Pubmed1996MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathwayRaingeaud, JWhitmarsh, AJBarrett, TDerijard, BDavis, RJMol Cell Biol 16:1247-55inferred by electronic annotationIEAGOIEA

Phosphorylated MKK3/MKK6 migrates to nucleus

Reactome DB_ID: 10516144

O-phospho-L-serine at 189 (in Homo sapiens)

189

EQUAL

O-phospho-L-threonine at 193 (in Homo sapiens)

193

EQUAL

347

EQUAL

Reactome DB_ID: 10516150

O-phospho-L-serine at 189 (in Homo sapiens)

189

EQUAL

O-phospho-L-threonine at 193 (in Homo sapiens)

193

EQUAL

347

EQUAL

Reactome Database ID Release 7510516154Database 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=10516154ReactomeR-DME-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-DME-450296.1The 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.

7535770Pubmed1995Pro-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 270:7420-69768359Pubmed1998Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2Ben-Levy, RHooper, SWilson, RPaterson, HFMarshall, CJCurr Biol 8:1049-57inferred by electronic annotationIEAGOIEA

2.7.12.2

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

Reactome DB_ID: 10516164

p38 MAPK:MAPKAPK2,3 [nucleoplasm]

p38 MAPK:MAPKAPK2,3

Reactome DB_ID: 10516160

UniProt:O61443p38b

UniProtO61443

EQUAL

364

EQUAL

Reactome DB_ID: 10516108

UniProt:P49071MAPk-Ak2

UniProtP49071

EQUAL

400

EQUAL

Reactome Database ID Release 7510516164Database 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=10516164ReactomeR-DME-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-DME-450269.1

Reactome DB_ID: 29358

Reactome DB_ID: 10516112

p-p38 MAPK: MAPKAPK2,3 [nucleoplasm]

p-p38 MAPK: MAPKAPK2,3

Reactome DB_ID: 10501922

O-phospho-L-threonine at 180 (in Homo sapiens)

180

EQUAL

O4'-phospho-L-tyrosine at 182 (in Homo sapiens)

182

EQUAL

364

EQUAL

Reactome DB_ID: 10516108

EQUAL

400

EQUAL

Reactome Database ID Release 7510516112Database 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=10516112ReactomeR-DME-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-DME-450213.1

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10516150

O-phospho-L-serine at 189 (in Homo sapiens)

189

EQUAL

O-phospho-L-threonine at 193 (in Homo sapiens)

193

EQUAL

347

EQUAL

GO0004708

GO molecular function

Reactome Database ID Release 7510516165Database 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=10516165Reactome Database ID Release 7510516167Database 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=10516167ReactomeR-DME-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-DME-450333.1The 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.

inferred by electronic annotationIEAGOIEA

2.7.11

Active p38 MAPK phosphorylates MAPKAPK2 or 3

Reactome DB_ID: 10516112

Reactome DB_ID: 29358

Reactome DB_ID: 10516118

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

p-p38 MAPK:p-MAPKAPK2/3

Reactome DB_ID: 10501922

O-phospho-L-threonine at 180 (in Homo sapiens)

180

EQUAL

O4'-phospho-L-tyrosine at 182 (in Homo sapiens)

182

EQUAL

364

EQUAL

Reactome DB_ID: 10516114

O-phospho-L-threonine at 222 (in Homo sapiens)

222

EQUAL

O-phospho-L-serine at 272 (in Homo sapiens)

272

EQUAL

O-phospho-L-threonine at 334 (in Homo sapiens)

334

EQUAL

400

EQUAL

Reactome Database ID Release 7510516118Database 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=10516118ReactomeR-DME-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-DME-450254.1

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10516112

GO0004674

GO molecular function

Reactome Database ID Release 7510516119Database 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=10516119Reactome Database ID Release 7510516121Database 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=10516121ReactomeR-DME-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-DME-450222.1Human 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.

15287722Pubmed2004Catalysis and function of the p38 alpha.MK2a signaling complexLukas, SMKroe, RRWildeson, JPeet, GWFrego, LDavidson, WIngraham, RHPargellis, CALabadia, MEWerneburg, BGBiochemistry 43:9950-6012171911Pubmed2002Structure 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 277:37401-58622688Pubmed19963pK, 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. 16:868-768774846Pubmed1996A 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. 392:209-1417255097Pubmed2007Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimerTer Haar, EPrabhakar, PLiu, XLepre, CJ Biol Chem 282:9733-917395714Pubmed2007Molecular basis of MAPK-activated protein kinase 2:p38 assemblyWhite, APargellis, CAStudts, JMWerneburg, BGFarmer BT, 2ndProc Natl Acad Sci U S A 104:6353-88626550Pubmed1996Identification 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. 271:8488-928846784Pubmed1995Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2Ben-Levy, RLeighton, IADoza, YNAttwood, PMorrice, NMarshall, CJCohen, PEMBO J 14:5920-30inferred by electronic annotationIEAGOIEA

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

Reactome DB_ID: 10516118

Reactome DB_ID: 10516123

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

Reactome DB_ID: 10503752

O-phospho-L-threonine at 222 (in Homo sapiens)

222

EQUAL

O-phospho-L-serine at 272 (in Homo sapiens)

272

EQUAL

O-phospho-L-threonine at 334 (in Homo sapiens)

334

EQUAL

400

EQUAL

Reactome DB_ID: 10503758

O-phospho-L-threonine at 180 (in Homo sapiens)

180

EQUAL

O4'-phospho-L-tyrosine at 182 (in Homo sapiens)

182

EQUAL

364

EQUAL

Reactome Database ID Release 7510516123Database 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=10516123ReactomeR-DME-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-DME-450241.1Reactome Database ID Release 7510516125Database 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=10516125ReactomeR-DME-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-DME-450257.1p38 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.

inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510568735Database 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=10568735ReactomeR-DME-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-DME-450302.1GO0000187

GO biological process

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.

10878576Pubmed2000p38 MAPK signalling cascades: ancient roles and new functionsMartin-Blanco, EBioessays 22:637-45inferred by electronic annotationIEAGOIEA

MAPK targets/ Nuclear events mediated by MAP kinases

ERK/MAPK targets

2.7.11

ERK1/2 phosphorylates MSK1

Reactome DB_ID: 10505828

UniProt:Q9V3I5JIL-1

UniProtQ9V3I5

EQUAL

802

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10505834

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

O-phospho-L-threonine at 581 (in Homo sapiens)

581

EQUAL

O-phospho-L-serine at 360 (in Homo sapiens)

360

EQUAL

O-phospho-L-serine at 212 (in Homo sapiens)

212

EQUAL

802

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10505876

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 7510505877Database 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=10505877Reactome Database ID Release 7510505881Database 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=10505881ReactomeR-DME-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-DME-198756.1MSK1 (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.

9687510Pubmed1998Mitogen- 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 17:4426-41inferred by electronic annotationIEAGOIEA

2.7.11

p38MAPK phosphorylates MSK1

Reactome DB_ID: 10505828

EQUAL

802

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10505834

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

O-phospho-L-threonine at 581 (in Homo sapiens)

581

EQUAL

O-phospho-L-serine at 360 (in Homo sapiens)

360

EQUAL

O-phospho-L-serine at 212 (in Homo sapiens)

212

EQUAL

802

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10501922

O-phospho-L-threonine at 180 (in Homo sapiens)

180

EQUAL

O4'-phospho-L-tyrosine at 182 (in Homo sapiens)

182

EQUAL

364

EQUAL

Reactome Database ID Release 7510505835Database 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=10505835Reactome Database ID Release 7510505837Database 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=10505837ReactomeR-DME-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-DME-198669.1MSK1 (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.

inferred by electronic annotationIEAGOIEA

2.7.11

ERK1/2/5 activate RSK1/2/3

Reactome DB_ID: 10505842

UniProt:Q9VR61S6kII

UniProtQ9VR61

EQUAL

735

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10505854

O-phospho-L-serine at 221 (in Homo sapiens)

221

EQUAL

O-phospho-L-serine at 363 (in Homo sapiens)

363

EQUAL

O-phospho-L-serine at 380 (in Homo sapiens)

380

EQUAL

O-phospho-L-serine at 732 (in Homo sapiens)

732

EQUAL

O-phospho-L-threonine at 359 (in Homo sapiens)

359

EQUAL

O-phospho-L-threonine at 573 (in Homo sapiens)

573

EQUAL

735

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10505876

Reactome Database ID Release 7510505879Database 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=10505879ReactomeR-DME-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-DME-198746.1The 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.

12832467Pubmed2003Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activityRoux, PPRichards, SABlenis, JMol Cell Biol 23:4796-80416626623Pubmed2006The MAP kinase ERK5 binds to and phosphorylates p90 RSKRanganathan, APearson, GWChrestensen, CASturgill, TWCobb, MHArch Biochem Biophys 449:8-16inferred by electronic annotationIEAGOIEA

ERKs are inactivated by protein phosphatase 2A

Reactome DB_ID: 113518

water [ChEBI:15377]

water

ChEBI15377Converted from EntitySet in Reactome

Reactome DB_ID: 10505876

Converted from EntitySet in Reactome

Reactome DB_ID: 10506116

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 DB_ID: 113550

hydrogenphosphate [ChEBI:43474]

hydrogenphosphate

[PO3(OH)](2-)HYDROGENPHOSPHATE IONhydrogen phosphate[P(OH)O3](2-)HPO4(2-)phosphateINORGANIC PHOSPHATE GROUP

ChEBI43474PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10506120

PP2A-ABdeltaC complex [nucleoplasm]

PP2A-ABdeltaC complex

Converted from EntitySet in Reactome

Reactome DB_ID: 10499184

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

Reactome DB_ID: 10506118

UniProt:Q8IN89wrd

UniProtQ8IN89

EQUAL

602

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 10499192

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 Database ID Release 7510506120Database 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=10506120ReactomeR-DME-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-DME-165970.1GO0004722

GO molecular function

Reactome Database ID Release 7510506121Database 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=10506121Reactome Database ID Release 7510506123Database 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=10506123ReactomeR-DME-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-DME-199959.1ERKs 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.

16456541Pubmed2006B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERKLetourneux, CRocher, GPorteu, FEMBO J 25:727-38inferred by electronic annotationIEAGOIEA

ERKs are inactivated

3.1.3.48

ERKs are inactivated by dual-specific phosphatases (DUSPs)

Reactome DB_ID: 113518

Converted from EntitySet in Reactome

Reactome DB_ID: 10505876

Converted from EntitySet in Reactome

Reactome DB_ID: 10506116

Reactome DB_ID: 113550

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10507058

ERK-specific DUSP [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMkp3 [nucleoplasm]MKP-like [nucleoplasm]

UniProtQ9VVW5UniProtX2JEB8GO0004725

GO molecular function

Reactome Database ID Release 7510507059Database 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=10507059Reactome Database ID Release 7510507075Database 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=10507075ReactomeR-DME-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-DME-203797.1Over 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.

17322878Pubmed2007A 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 39:503-12inferred by electronic annotationIEAGOIEA

INHIBITION

Reactome Database ID Release 7510507076Database 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=10507076

Reactome DB_ID: 10507073

VRK3:DUSP3 [nucleoplasm]

VRK3:DUSP3

Reactome DB_ID: 10507049

UniProt:X2JEB8MKP-like

EQUAL

185

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 10507071

Homologues of VRK3 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityball [nucleoplasm]BcDNA.LD23371 [nucleoplasm]

UniProtQ7KRY6UniProtQ7KMI3Reactome Database ID Release 7510507073Database 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=10507073ReactomeR-DME-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-DME-8942511.1

Reactome Database ID Release 7510568287Database 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=10568287ReactomeR-DME-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-DME-202670.1MAP 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.

15115656Pubmed2004Structure and regulation of MAPK phosphatasesFarooq, AZhou, MMCell Signal 16:769-79inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510568249Database 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=10568249ReactomeR-DME-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-DME-198753.1ERK/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.

inferred by electronic annotationIEAGOIEA

CREB phosphorylation

2.7.11

MSK1 activates CREB

Reactome DB_ID: 29358

Reactome DB_ID: 10505987

UniProt:Q9VWW0CrebB

UniProtQ9VWW0

EQUAL

341

EQUAL

Reactome DB_ID: 10505990

O-phospho-L-serine at 133 (in Homo sapiens)

133

EQUAL

341

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10505834

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

O-phospho-L-threonine at 581 (in Homo sapiens)

581

EQUAL

O-phospho-L-serine at 360 (in Homo sapiens)

360

EQUAL

O-phospho-L-serine at 212 (in Homo sapiens)

212

EQUAL

802

EQUAL

Reactome Database ID Release 7510506097Database 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=10506097Reactome Database ID Release 7510506106Database 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=10506106ReactomeR-DME-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-DME-199935.1MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB).

inferred by electronic annotationIEAGOIEA

2.7.11

MSK1 activates ATF1

Reactome DB_ID: 10506093

EQUAL

271

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10506096

O-phospho-L-serine at 63 (in Homo sapiens)

EQUAL

271

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10505834

O-phospho-L-serine at 376 (in Homo sapiens)

376

EQUAL

O-phospho-L-threonine at 581 (in Homo sapiens)

581

EQUAL

O-phospho-L-serine at 360 (in Homo sapiens)

360

EQUAL

O-phospho-L-serine at 212 (in Homo sapiens)

212

EQUAL

802

EQUAL

Reactome Database ID Release 7510506099Database 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=10506099ReactomeR-DME-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-DME-199910.1Cyclic-AMP-dependent transcription factor 1 (ATF1) can be phosphorylated at Serine 63 by MSK1, thus activating it.

12414794Pubmed2002ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth factor-induced c-jun expressionGupta, PankajPrywes, RonJ. Biol. Chem. 277:50550-6inferred by electronic annotationIEAGOIEA

2.7.11

RSK1/2/3 phosphorylates CREB at Serine 133

Reactome DB_ID: 29358

Reactome DB_ID: 10505987

EQUAL

341

EQUAL

Reactome DB_ID: 10505990

O-phospho-L-serine at 133 (in Homo sapiens)

133

EQUAL

341

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10505854

O-phospho-L-serine at 221 (in Homo sapiens)

221

EQUAL

O-phospho-L-serine at 363 (in Homo sapiens)

363

EQUAL

O-phospho-L-serine at 380 (in Homo sapiens)

380

EQUAL

O-phospho-L-serine at 732 (in Homo sapiens)

732

EQUAL

O-phospho-L-threonine at 359 (in Homo sapiens)

359

EQUAL

O-phospho-L-threonine at 573 (in Homo sapiens)

573

EQUAL

735

EQUAL

Reactome Database ID Release 7510506089Database 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=10506089Reactome Database ID Release 7510506091Database 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=10506091ReactomeR-DME-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-DME-199895.1CREB is phosphorylated at Serine 133 by RSK1/2/3.

9770464Pubmed1998Rsk-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 95:12202-7inferred by electronic annotationIEAGOIEA

2.7.11

MAPKAPK2 phosphorylates CREB at Serine 133

Reactome DB_ID: 29358

Reactome DB_ID: 10505987

EQUAL

341

EQUAL

Reactome DB_ID: 10505990

O-phospho-L-serine at 133 (in Homo sapiens)

133

EQUAL

341

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10506101

O-phospho-L-threonine at 222 (in Homo sapiens)

222

EQUAL

O-phospho-L-serine at 272 (in Homo sapiens)

272

EQUAL

400

EQUAL

Reactome Database ID Release 7510506102Database 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=10506102Reactome Database ID Release 7510506104Database 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=10506104ReactomeR-DME-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-DME-199917.1p38 MAPK activation leads to CREB Serine 133 phosphorylation through the activation of MAPKAP kinase 2 or the closely related MAPKAP kinase 3.

7551568Pubmed1995Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signalsBonni, AGinty, D DDudek, HGreenberg, M EMol. Cell. Neurosci. 6:168-83inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510568285Database 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=10568285ReactomeR-DME-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-DME-199920.1Nerve 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.

inferred by electronic annotationIEAGOIEA

Activation of the AP-1 family of transcription factors

2.7.11

Phosphorylated MAPKs phosphorylate ATF-2

Reactome DB_ID: 29358

Reactome DB_ID: 10501911

UniProt:Q2PE13Atf-2

UniProtQ2PE13

EQUAL

505

EQUAL

Reactome DB_ID: 10501915

O-phospho-L-threonine at 71 (in Homo sapiens)

EQUAL

O-phospho-L-threonine at 69 (in Homo sapiens)

EQUAL

505

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10501944

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 PhysicalEntityphospho-p38b [nucleoplasm]phospho-bsk [nucleoplasm]

Reactome Database ID Release 7510501945Database 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=10501945Reactome Database ID Release 7510501947Database 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=10501947ReactomeR-DME-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-DME-168053.1At 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'.

inferred by electronic annotationIEAGOIEA

2.7.11

Activated JNKs phosphorylate c-JUN

Reactome DB_ID: 10501951

UniProt:P18289 Jra

Jra

junCG2275JraFUNCTION Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3' (PubMed:1696724, PubMed:2116361). Plays a role in dorsal closure (PubMed:9224723).SUBUNIT Heterodimer with kay/Fra (PubMed:1696724, PubMed:2116361). The kay-Jra complex is bound more stably to the AP-1 site than either of the two proteins alone (PubMed:2116361). Interacts with Atf3; the interaction enhances the DNA-binding activity of Atf3 (PubMed:20023169).TISSUE SPECIFICITY During embryogenesis, expression is elevated in the amnioserosa, in the cells of the dorsolateral epidermis during and following germ-band retraction, in the cells at the leading dorsal edge of the epidermis and in the cells along the cephalic furrow (at protein level).DEVELOPMENTAL STAGE Expressed during embryonic development.DISRUPTION PHENOTYPE Death in mid to late embryogenesis with large anterior and dorsal holes.SIMILARITY Belongs to the bZIP family. Jun subfamily.

UniProtP18289

EQUAL

331

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10501955

O-phospho-L-serine at 63 (in Homo sapiens)

EQUAL

O-phospho-L-serine at 73 (in Homo sapiens)

EQUAL

331

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10501930

O-phospho-L-threonine at unknown position

O4'-phospho-L-tyrosine at unknown position

EQUAL

427

EQUAL

GO0004705

GO molecular function

Reactome Database ID Release 7510501956Database 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=10501956Reactome Database ID Release 7510501958Database 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=10501958ReactomeR-DME-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-DME-168136.1JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus.

18793328Pubmed2008c-Jun expression, activation and function in neural cell death, inflammation and repairRaivich, GJ Neurochem 107:898-9069561845Pubmed1998Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to developmentIp, YTDavis, RJCurr Opin Cell Biol 10:205-1910871633Pubmed2000c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activityDennler, SPrunier, CFerrand, NGauthier, JMAtfi, AJ Biol Chem 275:28858-65inferred by electronic annotationIEAGOIEA

2.7.11

c-FOS activation by phospho ERK1/2

Reactome DB_ID: 10516156

UniProt:P21525 kay

kay

kayCG15509FraFUNCTION Developmentally regulated transcription factor AP-1 binds and recognizes the enhancer DNA sequence: 5'-TGA[CG]TCA-3'. May play a role in the function or determination of a particular subset of cells in the developing embryo. It is able to carry out its function either independently of or in conjunction with Jra.SUBUNIT Homodimer. Heterodimer with Jra. The kay-Jra heterodimer binds more stably to the AP-1 site than either of the two proteins alone.TISSUE SPECIFICITY Early expression in the embryo is mesodermal and some of this expression is localized to a region surrounding the cephalic furrow. Later in embryonic development expression is ectodermal, corresponding to muscle attachment sites. Also observed in part of the mid- and hindgut and in the anal pad.DEVELOPMENTAL STAGE Isoform A and isoform B are expressed both maternally and zygotically. Zygotically expressed throughout embryogenesis, until second larval instar. Isoform A is more highly expressed than isoform B.DISRUPTION PHENOTYPE Loss of isoform A causes embryonic lethality.MISCELLANEOUS Mammals typically have four copies of fos, Drosophila has a single gene with multiple transcription start sites giving rise to multiple protein isoforms.SIMILARITY Belongs to the bZIP family. Fos subfamily.

UniProtP21525

EQUAL

380

EQUAL

Reactome DB_ID: 29358

Reactome DB_ID: 10516133

O-phospho-L-serine at 362 (in Homo sapiens)

362

EQUAL

O-phospho-L-serine at 374 (in Homo sapiens)

374

EQUAL

O-phospho-L-threonine at 325 (in Homo sapiens)

325

EQUAL

O-phospho-L-threonine at 331 (in Homo sapiens)

331

EQUAL

380

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 10505876

Reactome Database ID Release 7510516158Database 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=10516158ReactomeR-DME-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-DME-450325.1The 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.

12134156Pubmed2002Molecular interpretation of ERK signal duration by immediate early gene productsMurphy, LOSmith, StuartChen, RHFingar, DCBlenis, JNat Cell Biol 4:556-647588633Pubmed1995The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cellsOkazaki, KSagata, NEMBO J 14:5048-59inferred by electronic annotationIEAGOIEA

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

Reactome DB_ID: 10501955

O-phospho-L-serine at 63 (in Homo sapiens)

EQUAL

O-phospho-L-serine at 73 (in Homo sapiens)

EQUAL

331

EQUAL

Reactome DB_ID: 10501915

O-phospho-L-threonine at 71 (in Homo sapiens)

EQUAL

O-phospho-L-threonine at 69 (in Homo sapiens)

EQUAL

505

EQUAL

Reactome DB_ID: 10502024

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

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

Reactome DB_ID: 10501955

O-phospho-L-serine at 63 (in Homo sapiens)

EQUAL

O-phospho-L-serine at 73 (in Homo sapiens)

EQUAL

331

EQUAL

Reactome DB_ID: 10501915

O-phospho-L-threonine at 71 (in Homo sapiens)

EQUAL

O-phospho-L-threonine at 69 (in Homo sapiens)

EQUAL

505

EQUAL

Reactome Database ID Release 7510502024Database 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=10502024ReactomeR-DME-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-DME-450262.1Reactome Database ID Release 7510502026Database 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=10502026ReactomeR-DME-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-DME-168440.1At 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.

9030721Pubmed1997Regulatory 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 243:49-57inferred by electronic annotationIEAGOIEA

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

Reactome DB_ID: 10501955

O-phospho-L-serine at 63 (in Homo sapiens)

EQUAL

O-phospho-L-serine at 73 (in Homo sapiens)

EQUAL

331

EQUAL

Reactome DB_ID: 10516133

O-phospho-L-serine at 362 (in Homo sapiens)

362

EQUAL

O-phospho-L-serine at 374 (in Homo sapiens)

374

EQUAL

O-phospho-L-threonine at 325 (in Homo sapiens)

325

EQUAL

O-phospho-L-threonine at 331 (in Homo sapiens)

331

EQUAL

380

EQUAL

Reactome DB_ID: 10516135

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

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

Reactome DB_ID: 10501955

O-phospho-L-serine at 63 (in Homo sapiens)

EQUAL

O-phospho-L-serine at 73 (in Homo sapiens)

EQUAL

331

EQUAL

Reactome DB_ID: 10516133

O-phospho-L-serine at 362 (in Homo sapiens)

362

EQUAL

O-phospho-L-serine at 374 (in Homo sapiens)

374

EQUAL

O-phospho-L-threonine at 325 (in Homo sapiens)

325

EQUAL

O-phospho-L-threonine at 331 (in Homo sapiens)

331

EQUAL

380

EQUAL

Reactome Database ID Release 7510516135Database 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=10516135ReactomeR-DME-450327

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-DME-450327.1Reactome Database ID Release 7510516137Database 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=10516137ReactomeR-DME-450292

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-DME-450292.1The 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).

7816143Pubmed1995Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNAGlover, JNHarrison, SCNature 373:257-61inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510567895Database 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=10567895ReactomeR-DME-450341

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-DME-450341.1GO0051090

GO biological process

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>

19167516Pubmed2009Translational regulation mechanisms of AP-1 proteinsVesely, PWStaber, PBHoefler, GKenner, LMutat Res 682:7-129069263Pubmed1997AP-1 function and regulationKarin, MLiu, ZZandi, ECurr Opin Cell Biol 9:240-67622446Pubmed1995The regulation of AP-1 activity by mitogen-activated protein kinasesKarin, MJ Biol Chem 270:16483-615564374Pubmed2004AP-1 subunits: quarrel and harmony among siblingsHess, JAngel, PSchorpp-Kistner, MJ Cell Sci 117:5965-73inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510567897Database 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=10567897ReactomeR-DME-450282

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-DME-450282.1MAPKs 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.

19767751Pubmed2009Phosphoproteomics reveals new ERK MAP kinase targets and links ERK to nucleoporin-mediated nuclear transportKosako, HYamaguchi, NAranami, CUshiyama, MKose, SImamoto, NTaniguchi, HNishida, EHattori, SNat Struct Mol Biol 16:1026-3512471242Pubmed2002Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinasesJohnson, GLLapadat, RScience 298:1911-216393692Pubmed2006The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functionsYoon, SSeger, RGrowth Factors 24:21-4417637696Pubmed2007Coordinating TLR-activated signaling pathways in cells of the immune systemBanerjee, AGerondakis, SImmunol Cell Biol 85:420-417158707Pubmed2006Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinasesBogoyevitch, MAKobe, BMicrobiol Mol Biol Rev 70:1061-95inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510567899Database 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=10567899ReactomeR-DME-450294

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-DME-450294.1GO0051403

GO biological process

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.

11861597Pubmed2002MAP kinases in the immune responseDong, CDavis, RJFlavell, RAAnnu Rev Immunol 20:55-7211242034Pubmed2001Mammalian MAP kinase signalling cascadesChang, LKarin, MNature 410:37-4019196711Pubmed2009Selectivity of docking sites in MAPK kinasesBardwell, AJFrankson, EBardwell, LJ Biol Chem 284:13165-73inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510567921Database 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=10567921ReactomeR-DME-166058

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-DME-166058.1GO0002755

GO biological process

The first known downstream component of TLR4 and TLR2 signaling is the adaptor MyD88. Another adapter MyD88-adaptor-like (Mal; also known as TIR-domain-containing adaptor protein or TIRAP) has also been described for TLR4 and TLR2 signaling. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR, whereas Mal lacks the DD. The TIR homotypic interactions bring adapters into contact with the activated TLRs, whereas the DD modules recruit serine/threonine kinases such as interleukin-1-receptor-associated kinase (IRAK). Recruitment of these protein kinases is accompanied by phosphorylation, which in turn results in the interaction of IRAKs with TNF-receptor-associated factor 6 (TRAF6). The oligomerization of TRAF6 activates TAK1, a member of the MAP3-kinase family, and this leads to the activation of the IkB kinases. These kinases, in turn, phosphorylate IkB, leading to its proteolytic degradation and the translocation of NF-kB to the nucleus. Concomitantly, members of the activator protein-1 (AP-1) transcription factor family, Jun and Fos, are activated, and both AP-1 transcription factors and NF-kB are required for cytokine production, which in turn produces downstream inflammatory effects.

15276183Pubmed2004MD-2: the Toll 'gatekeeper' in endotoxin signallingGangloff, MGay, Nicholas JTrends Biochem Sci 29:294-300inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510567923Database 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=10567923ReactomeR-DME-168179

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-DME-168179.1GO0038123

GO biological process

TLR1 is expressed by monocytes. TLR1 and TLR2 cotranslationally form heterodimeric complexes on the cell surface and in the cytosol. The TLR2:TLR1 complex recognizes Neisserial PorB and Mycobacterial triacylated lipoproteins and peptides, amongst others, triggering up-regulation of nuclear factor-kappaB production and apoptotic cascades. Such cooperation between TLR1 and TLR2 on the cell surface of normal human peripheral blood mononuclear cells, for instance, leads to the activation of pro-inflammatory cytokine secretion (Sandor et al. 2003).

12975352Pubmed2003Importance of extra- and intracellular domains of TLR1 and TLR2 in NFkappa B signalingSandor, FLatz, ERe, FMandell, LRepik, GGolenbock, DTEspevik, TKurt-Jones, EAFinberg, RWJ Cell Biol 162:1099-110inferred by electronic annotationIEAGOIEA

Toll Like Receptor TLR6:TLR2 Cascade

Reactome Database ID Release 7510567927Database 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=10567927ReactomeR-DME-168188

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-DME-168188.1GO0038124

GO biological process

TLR2 and TLR4 recognize different bacterial cell wall components. While TLR4 is trained onto Gram-negative lipopolysaccharide components, TLR2 - in combination with TLR6 - plays a major role in recognizing peptidoglycan wall products from Gram-positive bacteria, as well as Mycobacterial diacylated lipopeptides. In particular, TLR6 appears to participate in discriminating the subtle differences between dipalmitoyl and tripalmitoyl cysteinyl residues (Okusawa et al. 2004).

14977973Pubmed2004Relationship between structures and biological activities of mycoplasmal diacylated lipopeptides and their recognition by toll-like receptors 2 and 6Okusawa, TFujita, MNakamura, JInto, TYasuda, MYoshimura, AHara, YHasebe, AGolenbock, DTMorita, MKuroki, YOgawa, TShibata, KInfect Immun 72:1657-65inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 7510567925Database 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=10567925ReactomeR-DME-181438

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-DME-181438.1GO0034134

GO biological process

TLR2 is involved in recognition of peptidoglycan from gram-positive bacteria, bacterial lipoproteins, mycoplasma lipoprotein and mycobacterial products. It is quite possible that recognition of at least some other TLR2 ligands may be assisted by additional accessory proteins, particularly in association with TLR1 or TLR6. TLR2 is expressed constitutively on macrophages, dendritic cells, and B cells, and can be induced in some other cell types, including epithelial cells. TLR1 and TLR6, on the other hand, are expressed almost ubiquitously (Muzio et al. 2000). TLR2 may be a sensor and inductor of specific defense processes, including oxidative stress and cellular necrosis initially spurred by microbial compounds.

10820283Pubmed2000Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cellsMuzio, MBosisio, DPolentarutti, ND'amico, GStoppacciaro, AMancinelli, Rvan't Veer, CPenton-Rol, GRuco, LPAllavena, PMantovani, AJ Immunol 164:5998-6004inferred by electronic annotationIEAGOIEA