BioPAX pathway converted from "NOD1/2 Signaling Pathway" in the Reactome database.
NOD1/2 Signaling Pathway
NOD1/2 Signaling Pathway
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
iE-DAP elicits a NOD1 response
iE-DAP elicits a NOD1 response
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9900781
1
cytosol
GO
0005829
UniProt:D4ADT7
Nod1
Reactome
http://www.reactome.org
Rattus norvegicus
NCBI Taxonomy
10116
UniProt
D4ADT7
Chain Coordinates
1
EQUAL
953
EQUAL
Reactome DB_ID: 622271
1
gamma-D-glutamyl-meso-diaminopimelic acid [ChEBI:59271]
gamma-D-glutamyl-meso-diaminopimelic acid
ChEBI
59271
Reactome DB_ID: 9900783
1
NOD1:iE-DAP [cytosol]
NOD1:iE-DAP
Reactome DB_ID: 9900781
1
1
EQUAL
953
EQUAL
Reactome DB_ID: 622271
1
Reactome Database ID Release 81
9900783
Database 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=9900783
Reactome
R-RNO-168408
1
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-RNO-168408.1
Reactome Database ID Release 81
9900785
Database 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=9900785
Reactome
R-RNO-168400
1
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-RNO-168400.1
Early studies suggested that NOD1 and NOD2 responded to lipopolysaccharides (LPS), but this was later shown to be due to contamination of LPS with bacterial peptidoglycans (PGNs), the true elicitor for NODs. It is generally believed that PGNs bind NOD1 though this remains to be formally demonstrated. NOD1 senses PGN moieties with a minimal dipeptide structure of D-gamma-glutamyl-meso-diaminopimelic acid (iE-DAP), which is unique to PGN structures from all Gram-negative bacteria and certain Gram-positive bacteria, including the genus Listeria and Bacillus. Attachment of acyl residues enhances NOD1 stimulation several hundred fold, possibly by facilitating PGN entry into the cell (Hasegawa et al. 2007).
12796777
Pubmed
2003
An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid
Chamaillard, M
Hashimoto, M
Horie, Y
Masumoto, J
Qiu, S
Saab, L
Ogura, Y
Kawasaki, A
Fukase, K
Kusumoto, S
Valvano, MA
Foster, SJ
Mak, TW
Nunez, G
Inohara, N
Nat Immunol 4:702-7
17322292
Pubmed
2007
A role of lipophilic peptidoglycan-related molecules in induction of Nod1-mediated immune responses
Hasegawa, M
Kawasaki, A
Yang, K
Fujimoto, Y
Masumoto, J
Breukink, E
Nunez, G
Fukase, K
Inohara, N
J Biol Chem 282:11757-64
12791997
Pubmed
2003
Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan
Girardin, SE
Boneca, IG
Carneiro, LA
Antignac, A
Jéhanno, M
Viala, J
Tedin, K
Taha, MK
Labigne, A
Zähringer, U
Coyle, AJ
DiStefano, PS
Bertin, J
Sansonetti, PJ
Philpott, DJ
Science 300:1584-7
inferred by electronic annotation
IEA
GO
IEA
MDP elicits a NOD2 response
MDP elicits a NOD2 response
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 708341
1
muramyl dipeptide [ChEBI:59414]
muramyl dipeptide
ChEBI
59414
Reactome DB_ID: 9900791
1
UniProt:A0A0G2K4Z7
Nod2
UniProt
A0A0G2K4Z7
1
EQUAL
1040
EQUAL
Reactome DB_ID: 9900793
1
MDP:NOD2 [cytosol]
MDP:NOD2
Reactome DB_ID: 708341
1
Reactome DB_ID: 9900791
1
1
EQUAL
1040
EQUAL
Reactome Database ID Release 81
9900793
Database 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=9900793
Reactome
R-RNO-168414
1
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-RNO-168414.1
Reactome Database ID Release 81
9900807
Database 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=9900807
Reactome
R-RNO-168412
1
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-RNO-168412.1
Muramyl dipeptide (MDP) is an essential structural component of bacterial peptidoglycan (PGN) and the minimal elicitor recognized by NOD2. As MDP is present in nearly all bacteria NOD2 is a general sensor of bacteria. NOD2 has additionally been reported to respond to ssRNA (Sabbah et al. 2009) and play a role in T cell activation (Shaw et al. 2011).
12527755
Pubmed
2003
Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection
Girardin, SE
Boneca, IG
Viala, J
Chamaillard, M
Labigne, A
Thomas, G
Philpott, DJ
Sansonetti, PJ
J Biol Chem 278:8869-72
12514169
Pubmed
2003
Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease
Inohara, N
Ogura, Y
Fontalba, A
Gutierrez, O
Pons, F
Crespo, J
Fukase, K
Inamura, S
Kusumoto, S
Hashimoto, M
Foster, SJ
Moran, AP
Fernandez-Luna, JL
Nunez, G
J Biol Chem 278:5509-12
21251876
Pubmed
2011
The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation
Shaw, MH
Kamada, N
Warner, N
Kim, YG
Nunez, G
Trends Immunol 32:73-9
19701189
Pubmed
2009
Activation of innate immune antiviral responses by Nod2
Sabbah, A
Chang, TH
Harnack, R
Frohlich, V
Tominaga, K
Dube, PH
Xiang, Y
Bose, S
Nat Immunol 10:1073-80
inferred by electronic annotation
IEA
GO
IEA
Activated NOD1 oligomerizes
Activated NOD1 oligomerizes
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9900783
6
Reactome DB_ID: 9900787
1
NOD1:iE-DAP oligomer [cytosol]
NOD1:iE-DAP oligomer
Reactome DB_ID: 9900783
6
Reactome Database ID Release 81
9900787
Database 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=9900787
Reactome
R-RNO-622306
1
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-RNO-622306.1
Reactome Database ID Release 81
9923390
Database 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=9923390
Reactome
R-RNO-622310
1
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-RNO-622310.1
NOD1 is activated by iE-DAP in a LRR domain dependent manner. The LRR domain has a negative influence on NOD1 self-association (Inohara et al. 2000); binding of iE-DAP likely causes conformational changes that free the NACHT domain, allowing oligomerization and subsequent association of other proteins. Coimmunoprecipitation experiments demonstrate that NOD1 can interact with itself (Inohara et al. 1999) via the NACHT domain (Inohara et al. 2000). NACHT domains are part of the AAA+ domain family. Members of this family form hexamers or heptamers. Based on this observation, NOD1 and NOD2 are believed to form oligomers of this size (Martinon & Tschopp, 2005).
10329646
Pubmed
1999
Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB
Inohara, N
Koseki, T
del Peso, L
Hu, Y
Yee, C
Chen, S
Carrio, R
Merino, J
Liu, D
Ni, J
Nunez, G
J Biol Chem 274:14560-7
15967716
Pubmed
2005
NLRs join TLRs as innate sensors of pathogens
Martinon, F
Tschopp, Jürg
Trends Immunol 26:447-54
10880512
Pubmed
2000
An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways
Inohara, N
Koseki, T
Lin, J
del Peso, L
Lucas, PC
Chen, FF
Ogura, Y
Nunez, G
J Biol Chem 275:27823-31
inferred by electronic annotation
IEA
GO
IEA
Activated NOD2 oligomerizes
Activated NOD2 oligomerizes
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9900793
6
Reactome DB_ID: 9900795
1
MDP:NOD2 oligomer [cytosol]
MDP:NOD2 oligomer
Reactome DB_ID: 9900793
6
Reactome Database ID Release 81
9900795
Database 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=9900795
Reactome
R-RNO-708350
1
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-RNO-708350.1
Reactome Database ID Release 81
9923542
Database 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=9923542
Reactome
R-RNO-708349
1
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-RNO-708349.1
NOD2 is activated by MDP in a LRR domain dependent manner. Based on studies of NOD1 activation and structural data from the NLR-related scaffold Apaf-1, the LRR domain is believed to have a negative influence on NOD2 self-association (Inohara et al. 2000, Riedl & Salvesen 2007); binding of MDP is believed to cause conformational changes that free the NACHT domain, allowing oligomerization and subsequent association of other proteins. Coimmunoprecipitation experiments demonstrate that NOD1 can interact with itself (Inohara et al. 1999) via the NACHT domain (Inohara et al. 2000). NACHT domains are part of the AAA+ domain family. Members of this family form hexamers or heptamers. Based on these observations, NOD2 is generally believed to form hexamers or heptamers (Martinon & Tschopp, 2005). NOD2 oliogomerization has been observed in NOD2-transfected HEK293T cells (Zhao et al. 2007).
17377525
Pubmed
2007
The apoptosome: signalling platform of cell death
Riedl, SJ
Salvesen, Guy S.
Nat Rev Mol Cell Biol 8:405-13
17303577
Pubmed
2007
Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells
Zhao, L
Kwon, MJ
Huang, S
Lee, JY
Fukase, K
Inohara, N
Hwang, DH
J Biol Chem 282:11618-28
inferred by electronic annotation
IEA
GO
IEA
Activated NOD oligomer recruites RIP2 (RICK)
Activated NOD oligomer recruites RIP2 (RICK)
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Converted from EntitySet in Reactome
Reactome DB_ID: 9900797
1
PAMP:NOD oligomer [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
Reactome DB_ID: 9900801
6
UniProt:G3V783
Ripk2
UniProt
G3V783
1
EQUAL
540
EQUAL
Reactome DB_ID: 9900803
1
PAMP:NOD oligomer:RIP2 [cytosol]
PAMP:NOD oligomer:RIP2
Converted from EntitySet in Reactome
Reactome DB_ID: 9900797
1
Reactome DB_ID: 9900801
6
1
EQUAL
540
EQUAL
Reactome Database ID Release 81
9900803
Database 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=9900803
Reactome
R-RNO-168409
1
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-RNO-168409.1
Reactome Database ID Release 81
9900805
Database 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=9900805
Reactome
R-RNO-168405
1
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-RNO-168405.1
NOD1 and NOD2 (NOD) interact with the inflammatory kinase RIP2 (RICK) via a homophilic association between CARD domains (Inohara et al. 1999, Ogura et al. 2001). This has the effect of bringing several RIP2 molecules into close proximity, enhancing RIP2-RIP2 interactions (Inohara et al. 2000), a key step in what is termed the 'Induced Proximity Model' for NOD activation of NFkappaB. Note that though the interaction of every NOD with RIP2 is implied here this may not be required for RIP2 activation. RIP2 recruitment leads to subsequent activation of NFkappaB. The kinase activity of RIP2 was initially described as not required (Inohara et al. 2000) but subsequently suggested to be involved in determining signal strength (Windheim et al. 2007) and recently found to be essential for maintaining RIP2 stability and it's role in mediating NOD signaling (Nembrini et al. 2009).
19473975
Pubmed
2009
The kinase activity of Rip2 determines its stability and consequently Nod1- and Nod2-mediated immune responses
Nembrini, C
Kisielow, J
Shamshiev, AT
Tortola, L
Coyle, AJ
Kopf, M
Marsland, BJ
J Biol Chem 284:19183-8
11087742
Pubmed
2001
Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB
Ogura, Y
Inohara, N
Benito, A
Chen, FF
Yamaoka, S
Nunez, G
J Biol Chem 276:4812-8
17348859
Pubmed
2007
Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide
Windheim, M
Lang, C
Peggie, M
Plater, LA
Cohen, P
Biochem J 404:179-90
10224040
Pubmed
1999
Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB
Bertin, J
Nir, WJ
Fischer, CM
Tayber, OV
Errada, PR
Grant, JR
Keilty, JJ
Gosselin, ML
Robison, KE
Wong, GH
Glucksmann, MA
DiStefano, PS
J Biol Chem 274:12955-8
inferred by electronic annotation
IEA
GO
IEA
RIP2 binds NEMO
RIP2 binds NEMO
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9900803
1
Reactome DB_ID: 9900670
1
UniProt:Q6TMG5
Ikbkg
UniProt
Q6TMG5
1
EQUAL
419
EQUAL
Reactome DB_ID: 9923476
1
PAMP:NOD oligomer:RIP2:NEMO [cytosol]
PAMP:NOD oligomer:RIP2:NEMO
Reactome DB_ID: 9900803
1
Reactome DB_ID: 9900670
1
1
EQUAL
419
EQUAL
Reactome Database ID Release 81
9923476
Database 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=9923476
Reactome
R-RNO-688994
1
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-RNO-688994.1
Reactome Database ID Release 81
9923478
Database 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=9923478
Reactome
R-RNO-622415
1
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-RNO-622415.1
An intermediate region located between the CARD and kinase domains mediates the interaction of RIP2 with the IKK complex regulatory subunit NEMO. This interaction is presumed to link NOD1:RIP2 to the IKK complex, ultimately leading to the phosphorylation of IkappaB-alpha and the activation of NF-kappaB (Inohara et al. 2000). Although every NOD molecule in the oligomeric complex is represented as binding RIP2, binding to every member of the complex may not be required for subsequent signaling events.
18079694
Pubmed
2008
A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation
Hasegawa, M
Fujimoto, Y
Lucas, PC
Nakano, H
Fukase, K
Nunez, G
Inohara, N
EMBO J 27:373-83
inferred by electronic annotation
IEA
GO
IEA
6.3.2.19
RIP2 induces K63-linked ubiquitination of NEMO
RIP2 induces K63-linked ubiquitination of NEMO
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9900861
1
K63polyUb [cytosol]
K63polyUb
Reactome DB_ID: 9923476
1
Reactome DB_ID: 9923589
1
PAMP:NOD oligomer:RIP2:K63-Ub-K285-NEMO [cytosol]
PAMP:NOD oligomer:RIP2:K63-Ub-K285-NEMO
Reactome DB_ID: 9900803
1
Reactome DB_ID: 9923587
1
ubiquitinylated lysine (K63polyUb [cytosol]) at 285 (in Homo sapiens)
285
EQUAL
ubiquitinylated lysine [MOD:01148]
1
EQUAL
419
EQUAL
Reactome Database ID Release 81
9923589
Database 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=9923589
Reactome
R-RNO-741389
1
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-RNO-741389.1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 9923519
TRAF6 E3/E2 ubiquitin ligase complex [cytosol]
TRAF6 E3/E2 ubiquitin ligase complex
Reactome DB_ID: 9907833
1
UBE2N:UBE2V1 [cytosol]
UBE2N:UBE2V1
Reactome DB_ID: 9907831
1
UniProt:D3ZFY8
LOC100912618
UniProt
D3ZFY8
2
EQUAL
147
EQUAL
Reactome DB_ID: 9907827
1
UniProt:Q9EQX9
Ube2n
UniProt
Q9EQX9
1
EQUAL
152
EQUAL
Reactome Database ID Release 81
9907833
Database 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=9907833
Reactome
R-RNO-202463
1
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-RNO-202463.1
Reactome DB_ID: 9900542
1
UniProt:B5DF45
Traf6
UniProt
B5DF45
1
EQUAL
522
EQUAL
Reactome Database ID Release 81
9923519
Database 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=9923519
Reactome
R-RNO-1248657
1
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-RNO-1248657.1
GO
0004842
GO molecular function
Reactome Database ID Release 81
9923590
Database 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=9923590
Reactome Database ID Release 81
9923592
Database 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=9923592
Reactome
R-RNO-741386
1
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-RNO-741386.1
RIP2 induces the K63-linked ubiquitination of NEMO at K285 and K399, positively modulating subsequent NF-kappaB activation (Abbot et al. 2007). TRAF6 E3 ligase is capable of performing this ubiquitination step when overexpressed in HEK239 cells, and this effect is blocked if RIP2 siRNA is co-transfected, but small interfering RNA (siRNA) experiments indicate that there are additional E3 ligases that can substitute for TRAF6 in NEMO ubiquitination. In addition to TRAF6, the K63-specific E2 ligase Ubc13 is required for NEMO ubiquitination suggesting a common mechanism for NEMO ubiquitination in NOD and TLR signaling.
17562858
Pubmed
2007
Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains
Abbott, Derek W
Yang, Y
Hutti, JE
Madhavarapu, S
Kelliher, MA
Cantley, Lewis C
Mol Cell Biol 27:6012-25
inferred by electronic annotation
IEA
GO
IEA
CYLD deubiquitinates NEMO
CYLD deubiquitinates NEMO
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9923589
1
Reactome DB_ID: 9900861
1
Reactome DB_ID: 9923476
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 9897186
UniProt:Q66H62
Cyld
UniProt
Q66H62
1
EQUAL
956
EQUAL
GO
0061578
GO molecular function
Reactome Database ID Release 81
9923593
Database 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=9923593
Reactome Database ID Release 81
9923595
Database 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=9923595
Reactome
R-RNO-741411
1
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-RNO-741411.1
RIP2-induced ubiquitination of NEMO and consequent NFkappaB activation can be reversed in a dose-responsive manner by the deubiquitinase CYLD, suggesting that CYLD negatively regulates RIP2-induced NEMO ubiquitinylation.
15620648
Pubmed
2004
The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO
Abbott, Derek W
Wilkins, A
Asara, JM
Cantley, Lewis C
Curr Biol 14:2217-27
12917691
Pubmed
2003
The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination
Kovalenko, A
Chable-Bessia, C
Cantarella, G
Israel, A
Wallach, D
Courtois, G
Nature 424:801-5
inferred by electronic annotation
IEA
GO
IEA
RIP2 is K63 polyubiquitinated
RIP2 is K63 polyubiquitinated
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9900861
6
Reactome DB_ID: 9923476
1
Reactome DB_ID: 9921638
1
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO [cytosol]
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO
Reactome DB_ID: 9921636
1
PAMP:NOD oligomer:K63-Ub-RIP2 [cytosol]
PAMP:NOD oligomer:K63-Ub-RIP2
Reactome DB_ID: 9921634
6
ubiquitinylated lysine (K63polyUb [cytosol]) at 209 (in Homo sapiens)
209
EQUAL
1
EQUAL
540
EQUAL
Converted from EntitySet in Reactome
Reactome DB_ID: 9900797
1
Reactome Database ID Release 81
9921636
Database 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=9921636
Reactome
R-RNO-706482
1
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-RNO-706482.1
Reactome DB_ID: 9900670
1
1
EQUAL
419
EQUAL
Reactome Database ID Release 81
9921638
Database 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=9921638
Reactome
R-RNO-706480
1
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-RNO-706480.1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 9923525
RIP2 ubiquitin ligases [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
Itch [cytosol]
UniProt
A0A0G2K9T1
GO
0019787
GO molecular function
Reactome Database ID Release 81
9923526
Database 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=9923526
Reactome Database ID Release 81
9923528
Database 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=9923528
Reactome
R-RNO-688137
1
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-RNO-688137.1
The close physical proximity of RIP2 proteins that results from NOD oligomerization triggers the conjugation of lysine (K)-63 linked polyubiquitin chains onto RIP2. Ubiquitination at K209 within the kinase domain was required for subsequent NFkappaB signaling (Hasegawa et al. 2008). The identity of the ubiquitin ligase responsible is an open question, with several candidates capable of RIP2 ubiquitination. TRAF6 has been reported as the ubiquitin ligase responsible (Yang et al. 2007) but subsequent reports suggest it is not responsible (see Tao et al. 2009 and Bertrand et al. 2009). Other candidates include the HECT-domain containing E3 ubiquitin ligase ITCH, which is able to K63 ubiquitinate RIP2 (at an undetermined site that is not K209) and is required for optimal NOD2:RIP2-induced p38 and JNK activation, while inhibiting NOD2:RIP2-induced NFkappaB activation (Tao et al. 2009). The Baculoviral IAP repeat-containing proteins (Birc/cIAP) 2 and 3 have also been shown capable of RIP2 ubiquitination and required for NOD2 signaling (Bertrand et al. 2009). It has been suggested that ITCH and a K209 E3 ligase compete for ubiquitination of RIP2, so that a subset of RIP2 becomes ubiquitinated on K209 to stimulate NEMO ubiquitination and subsequent NFkappaB activation while a second subset of RIP2 is polyubiquitinated by ITCH to activate JNK and p38 signaling (Tao et al. 2009).
19464198
Pubmed
2009
Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2
Bertrand, MJ
Doiron, K
Labbé, K
Korneluk, RG
Barker, PA
Saleh, M
Immunity 30:789-801
17947236
Pubmed
2007
NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2
Yang, Y
Yin, C
Pandey, A
Abbott, Derek W
Sassetti, C
Kelliher, MA
J Biol Chem 282:36223-9
19592251
Pubmed
2009
ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways
Tao, M
Scacheri, PC
Marinis, JM
Harhaj, EW
Matesic, LE
Abbott, Derek W
Curr Biol 19:1255-63
inferred by electronic annotation
IEA
GO
IEA
TNFAIP3 (A20) deubiquitinates RIP2
TNFAIP3 (A20) deubiquitinates RIP2
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9921638
1
Reactome DB_ID: 9900861
6
Reactome DB_ID: 9923476
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 9897190
UniProt:M0R7V5
Tnfaip3
UniProt
M0R7V5
1
EQUAL
790
EQUAL
Reactome Database ID Release 81
9923511
Database 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=9923511
Reactome Database ID Release 81
9923513
Database 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=9923513
Reactome
R-RNO-688136
1
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-RNO-688136.1
The deubiquitinase A20 is a negative feedback regulator of inflammatory responses, induced by NFkappaB activation (Krikos et al. 1992) and NOD stimulation (Masumoto et al. 2006). A20 can deubiquitinate RIP2 and restricts NOD2 induced signals (Hitosumatsu et al. 2008).
1381359
Pubmed
1992
Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by kappa B elements
Krikos, A
Laherty, CD
Dixit, VM
J Biol Chem 267:17971-6
16418393
Pubmed
2006
Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo
Masumoto, J
Yang, K
Varambally, S
Hasegawa, M
Tomlins, SA
Qiu, S
Fujimoto, Y
Kawasaki, A
Foster, SJ
Horie, Y
Mak, TW
Nunez, G
Chinnaiyan, AM
Fukase, K
Inohara, N
J Exp Med 203:203-13
18342009
Pubmed
2008
The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals
Hitotsumatsu, O
Ahmad, RC
Tavares, R
Wang, M
Philpott, D
Turer, EE
Lee, BL
Shiffin, N
Advincula, R
Malynn, BA
Werts, C
Ma, A
Immunity 28:381-90
inferred by electronic annotation
IEA
GO
IEA
K63 polyubiquitinated RIP2 associates with the TAK1 complex
K63 polyubiquitinated RIP2 associates with the TAK1 complex
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9921638
1
Reactome DB_ID: 9923534
1
plasma membrane
GO
0005886
TAK1 complex [plasma membrane]
TAK1 complex
Reactome DB_ID: 9921050
1
UniProt:P0C8E4
Map3k7
UniProt
P0C8E4
1
EQUAL
606
EQUAL
Converted from EntitySet in Reactome
Reactome DB_ID: 9923532
1
TAB2,TAB3 [plasma membrane]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
Tab2 [plasma membrane]
Tab3 [plasma membrane]
UniProt
Q5U303
UniProt
F1M1D2
Reactome DB_ID: 9921054
1
UniProt:A0A0U1RRU5
Tab1
UniProt
A0A0U1RRU5
1
EQUAL
504
EQUAL
Reactome Database ID Release 81
9923534
Database 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=9923534
Reactome
R-RNO-8947970
1
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-RNO-8947970.1
Reactome DB_ID: 9923536
1
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex [plasma membrane]
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex
Reactome DB_ID: 9921638
1
Reactome DB_ID: 9923534
1
Reactome Database ID Release 81
9923536
Database 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=9923536
Reactome
R-RNO-706478
1
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-RNO-706478.1
Reactome Database ID Release 81
9923538
Database 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=9923538
Reactome
R-RNO-688985
1
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-RNO-688985.1
K63-polyubiquitinated RIP2 is able to recruit the components of the TAK1 complex, which consists of TAK1, TAB1 and TAB2.
inferred by electronic annotation
IEA
GO
IEA
TAK1 is activated
TAK1 is activated
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9923536
1
Reactome DB_ID: 9921640
1
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex [cytosol]
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex
Reactome DB_ID: 9921638
1
Reactome DB_ID: 9921064
1
TAK1 complex [cytosol]
TAK1 complex
Converted from EntitySet in Reactome
Reactome DB_ID: 9921062
1
TAB2,TAB3 [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
Tab3 [cytosol]
Tab2 [cytosol]
Reactome DB_ID: 9921050
1
1
EQUAL
606
EQUAL
Reactome DB_ID: 9921054
1
1
EQUAL
504
EQUAL
Reactome Database ID Release 81
9921064
Database 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=9921064
Reactome
R-RNO-446878
1
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-RNO-446878.1
Reactome Database ID Release 81
9921640
Database 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=9921640
Reactome
R-RNO-706477
1
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-RNO-706477.1
Reactome Database ID Release 81
9923540
Database 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=9923540
Reactome
R-RNO-706479
1
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-RNO-706479.1
The TAK1 complex consists of Transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004).
15327770
Pubmed
2004
TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains
Kanayama, A
Seth, RB
Sun, L
Ea, CK
Hong, M
Shaito, A
Chiu, YH
Deng, L
Chen, ZJ
Mol Cell 15:535-48
10702308
Pubmed
2000
TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop
Kishimoto, K
Matsumoto, K
Ninomiya-Tsuji, J
J Biol Chem 275:7359-64
14633987
Pubmed
2003
Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling
Ishitani, T
Takaesu, G
Ninomiya-Tsuji, J
Shibuya, H
Gaynor, RB
Matsumoto, K
EMBO J 22:6277-88
inferred by electronic annotation
IEA
GO
IEA
2.7.11.25
TAK1 phosphorylates MKK6
TAK1 phosphorylates MKK6
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9921655
1
UniProt:Q925D6
Map2k6
UniProt
Q925D6
1
EQUAL
334
EQUAL
Reactome DB_ID: 113592
2
ATP(4-) [ChEBI:30616]
ATP(4-)
Adenosine 5'-triphosphate
atp
ATP
ChEBI
30616
Reactome DB_ID: 9921602
1
O-phospho-L-serine at 207 (in Homo sapiens)
207
EQUAL
O-phospho-L-serine [MOD:00046]
O-phospho-L-threonine at 211 (in Homo sapiens)
211
EQUAL
O-phospho-L-threonine [MOD:00047]
1
EQUAL
334
EQUAL
Reactome DB_ID: 29370
2
ADP(3-) [ChEBI:456216]
ADP(3-)
ADP trianion
5'-O-[(phosphonatooxy)phosphinato]adenosine
ADP
ChEBI
456216
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 9921064
GO
0004709
GO molecular function
Reactome Database ID Release 81
9923575
Database 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=9923575
Reactome Database ID Release 81
9923577
Database 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=9923577
Reactome
R-RNO-727819
1
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-RNO-727819.1
Within the TAK1 complex (TAK1 plus TAB1 and TAB2/3) activated TAK1 phosphorylates IKKB, MAPK kinase 6 (MKK6) and other MAPKs to activate the NFkappaB and MAPK signaling pathways. TAB2 within the TAK1 complex can be linked to polyubiquitinated TRAF6; current models of IL-1 signaling suggest that the TAK1 complex is linked to TRAF6, itself complexed with polyubiquitinated IRAK1 which is linked via NEMO to the IKK complex. The TAK1 complex is also essential for NOD signaling; NOD receptors bind RIP2 which recruits the TAK1 complex (Hasegawa et al. 2008).
11460167
Pubmed
2001
TAK1 is a ubiquitin-dependent kinase of MKK and IKK
Wang, C
Deng, L
Hong, M
Akkaraju, GR
Inoue, J
Chen, ZJ
Nature 412:346-51
inferred by electronic annotation
IEA
GO
IEA
NOD1 induced apoptosis is mediated by RIP2 and CARD8
NOD1 induced apoptosis is mediated by RIP2 and CARD8
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Converted from EntitySet in Reactome
Reactome DB_ID: 9923484
1
Long prodomain caspases [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
Casp8 [cytosol]
UniProt
Q9JHX4
Reactome DB_ID: 9900783
1
Reactome DB_ID: 9923486
1
NOD1:iE-DAP:Long prodomain caspases [cytosol]
NOD1:iE-DAP:Long prodomain caspases
Converted from EntitySet in Reactome
Reactome DB_ID: 9923484
1
Reactome DB_ID: 9900783
1
Reactome Database ID Release 81
9923486
Database 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=9923486
Reactome
R-RNO-622417
1
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-RNO-622417.1
Reactome Database ID Release 81
9923488
Database 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=9923488
Reactome
R-RNO-622420
1
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-RNO-622420.1
NOD1 was found to coimmunoprecipitate with several procaspases containing long prodomains with CARDs or DEDs, including caspase-1, caspase-2, caspase-4, caspase-8, and caspase-9, but not those with short prodomains like caspase-3 or caspase-7. Deletions of caspase-9 determined that the CARD domain was required for this interaction (Inohara et al. 1999). More recently, NOD1 activation of apoptosis was shown to require the RIP2-dependent activation of caspase-8, this effect being inhibited by CASP8 and FADD-like apoptosis regulator, also called FLICE-inhibitory protein, FLIP or CLARP (da Silva Correia et al. 2007), which is a specific inhibitor of caspase-8 (Irmler et al. 1997).
17186025
Pubmed
2007
Regulation of Nod1-mediated signaling pathways
da Silva Correia, J
Miranda, Y
Leonard, N
Hsu, J
Ulevitch, RJ
Cell Death Differ 14:830-9
9217161
Pubmed
1997
Inhibition of death receptor signals by cellular FLIP
Irmler, M
Thome, M
Hahne, M
Schneider, P
Hofmann, K
Steiner, V
Bodmer, JL
Schröter, M
Burns, K
Mattmann, C
Rimoldi, D
French, LE
Tschopp, Jürg
Nature 388:190-5
inferred by electronic annotation
IEA
GO
IEA
2.7.12.2
Activation of p38 MAPK
Activation of p38 MAPK
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Converted from EntitySet in Reactome
Reactome DB_ID: 9931946
1
p38 MAPK [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
Reactome DB_ID: 113592
8
Converted from EntitySet in Reactome
Reactome DB_ID: 9931952
1
Phospho-p38 MAPK [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
Reactome DB_ID: 29370
8
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 9921602
O-phospho-L-serine at 207 (in Homo sapiens)
207
EQUAL
O-phospho-L-threonine at 211 (in Homo sapiens)
211
EQUAL
1
EQUAL
334
EQUAL
GO
0004708
GO molecular function
Reactome Database ID Release 81
9931953
Database 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=9931953
Reactome Database ID Release 81
9931955
Database 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=9931955
Reactome
R-RNO-1247960
1
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-RNO-1247960.1
p38 MAPK has 4 representative isoforms in humans, p38 alpha (Han et al. 1993), p38-beta (Jiang et al. 1996), p38-gamma (Lechner et al. 1996) and p38-delta (Hu et al. 1999). All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms (Zarubin & Han, 2005). p38 alpha and gamma are also activated by MKK3.
10066767
Pubmed
1999
Murine p38-delta mitogen-activated protein kinase, a developmentally regulated protein kinase that is activated by stress and proinflammatory cytokines
Hu, MC
Wang, YP
Mikhail, A
Qiu, WR
Tan, TH
J Biol Chem 274:7095-102
7693711
Pubmed
1993
Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14
Han, J
Lee, JD
Tobias, PS
Ulevitch, RJ
J Biol Chem 268:25009-14
8663524
Pubmed
1996
Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta)
Jiang, Y
Chen, C
Li, Z
Guo, W
Gegner, JA
Lin, S
Han, J
J Biol Chem 271:17920-6
9430721
Pubmed
1998
Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6
Enslen, H
Raingeaud, J
Davis, RJ
J Biol Chem 273:1741-8
8633070
Pubmed
1996
ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation
Lechner, C
Zahalka, MA
Giot, JF
Møller, NP
Ullrich, A
Proc Natl Acad Sci U S A 93:4355-9
15686620
Pubmed
2005
Activation and signaling of the p38 MAP kinase pathway
Zarubin, T
Han, J
Cell Res 15:11-8
inferred by electronic annotation
IEA
GO
IEA
AAMP binds NOD2
AAMP binds NOD2
This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><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>
Reactome DB_ID: 9900791
1
1
EQUAL
1040
EQUAL
Reactome DB_ID: 9989490
1
UniProt:G3V7V2
Aamp
UniProt
G3V7V2
1
EQUAL
434
EQUAL
Reactome DB_ID: 9989536
1
AAMP:NOD2 [cytosol]
AAMP:NOD2
Reactome DB_ID: 9900791
1
1
EQUAL
1040
EQUAL
Reactome DB_ID: 9989490
1
1
EQUAL
434
EQUAL
Reactome Database ID Release 81
9989536
Database 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=9989536
Reactome
R-RNO-9676152
1
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-RNO-9676152.1
Reactome Database ID Release 81
9989538
Database 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=9989538
Reactome
R-RNO-9676160
1
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-RNO-9676160.1
AAMP (Angio-associated migratory cell protein) binds the human nucleotide-binding domain, leucine rich repeat containing (NLR) family member NOD2. The interaction involves WD40 domains 2-4 of AAMP. NOD2 is critically involved in innate immune protection against a variety of different bacterial pathogens. AAMP negatively regulates, through an unknown mechanism, NOD2-mediated NF-κB activation in HEK293T cells (Bielig et al. 2009).
19535145
Pubmed
2009
A function for AAMP in Nod2-mediated NF-kappaB activation
Bielig, H
Zurek, B
Kutsch, A
Menning, M
Philpott, D J
Sansonetti, P J
Kufer, T A
Mol. Immunol. 46:2647-54
inferred by electronic annotation
IEA
GO
IEA
Reactome Database ID Release 81
9993061
Database 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=9993061
Reactome
R-RNO-168638
1
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-RNO-168638.1
GO
0070423
GO biological process
NOD1 is ubiquitously expressed, while NOD2 expression is restricted to monocytes, macrophages, dendritic cells, and intestinal Paneth cells (Inohara et al. 2005). NOD1 and NOD2 activation induces transcription of immune response genes, predominantly mediated by the proinflammatory transcriptional factor NFkappaB but also by AP-1 and Elk-1 (Inohara et al. 2005). NFkappaB translocates to the nucleus following release from IkappaB proteins. NOD1 and NOD2 signaling involves an interaction between their caspase-recruitment domain (CARD) and the CARD of the kinase RIPK2 (RIP2/RICK). This leads to the activation of the NFkappaB pathway and MAPK pathways (Windheim et al. 2007).<br>Activated NODs oligomerize via their NACHT domains, inducing physical proximity of RIP2 proteins that is believed to trigger their K63-linked polyubiquitination, facilitating recruitment of the TAK1 complex. RIP2 also recruits NEMO, bringing the TAK1 and IKK complexes into proximity, leading to NF-kappaB activation and activation of MAPK signaling. Recent studies have demonstrated that K63-linked regulatory ubiquitination of RIP2 is essential for the recruitment of TAK1 (Hasegawa et al. 2008, Hitosumatsu et al. 2008). As observed for toll-like receptor (TLR) signaling, ubiquitination can be removed by the deubiquitinating enzyme A20, thereby dampening NOD1/NOD2-induced NF-kappaB activation. NOD1 and NOD2 both induce K63-linked ubiquitination of RIP2, but NOD2-signaling appears to preferentially utilize the E3 ligase TRAF6, while TRAF2 and TRAF5 were shown to be important for NOD1-mediated signaling. In both cases, activation of NF-kappaB results in the upregulated transcription and production of inflammatory mediators.
18414735
Pubmed
2008
Signal transduction pathways used by NLR-type innate immune receptors
Kufer, TA
Mol Biosyst 4:380-6
18585455
Pubmed
2008
NOD-like receptors (NLRs): bona fide intracellular microbial sensors
Shaw, MH
Reimer, T
Kim, YG
Nunez, G
Curr Opin Immunol 20:377-82
18928408
Pubmed
2009
NOD-like receptors: role in innate immunity and inflammatory disease
Chen, G
Shaw, MH
Kim, YG
Nunez, G
Annu Rev Pathol 4:365-98
15952891
Pubmed
2005
NOD-LRR proteins: role in host-microbial interactions and inflammatory disease
Inohara, N
Chamaillard, M
McDonald, C
Nunez, G
Annu Rev Biochem 74:355-83
inferred by electronic annotation
IEA
GO
IEA