P58801 · RIPK2_MOUSE
- ProteinReceptor-interacting serine/threonine-protein kinase 2
- GeneRipk2
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids539 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Serine/threonine/tyrosine-protein kinase that plays an essential role in modulation of innate and adaptive immune responses (By similarity).
Acts as a key effector of NOD1 and NOD2 signaling pathways: upon activation by bacterial peptidoglycans, NOD1 and NOD2 oligomerize and recruit RIPK2 via CARD-CARD domains, leading to the formation of RIPK2 filaments (PubMed:17277144, PubMed:21469090, PubMed:30405132).
Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3, as well as 'Met-1'-linked (linear) polyubiquitination by the LUBAC complex, becoming a scaffolding protein for downstream effectors (PubMed:30405132).
'Met-1'-linked polyubiquitin chains attached to RIPK2 recruit IKBKG/NEMO, which undergoes 'Lys-63'-linked polyubiquitination in a RIPK2-dependent process (By similarity).
'Lys-63'-linked polyubiquitin chains attached to RIPK2 serve as docking sites for TAB2 and TAB3 and mediate the recruitment of MAP3K7/TAK1 to IKBKG/NEMO, inducing subsequent activation of IKBKB/IKKB (PubMed:17965022).
In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (By similarity).
The protein kinase activity is dispensable for the NOD1 and NOD2 signaling pathways (By similarity).
Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappa-B activation by NOD2 (By similarity).
Also involved in adaptive immunity: plays a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation (By similarity).
Plays a role in the inactivation of RHOA in response to NGFR signaling (PubMed:26646181).
Acts as a key effector of NOD1 and NOD2 signaling pathways: upon activation by bacterial peptidoglycans, NOD1 and NOD2 oligomerize and recruit RIPK2 via CARD-CARD domains, leading to the formation of RIPK2 filaments (PubMed:17277144, PubMed:21469090, PubMed:30405132).
Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3, as well as 'Met-1'-linked (linear) polyubiquitination by the LUBAC complex, becoming a scaffolding protein for downstream effectors (PubMed:30405132).
'Met-1'-linked polyubiquitin chains attached to RIPK2 recruit IKBKG/NEMO, which undergoes 'Lys-63'-linked polyubiquitination in a RIPK2-dependent process (By similarity).
'Lys-63'-linked polyubiquitin chains attached to RIPK2 serve as docking sites for TAB2 and TAB3 and mediate the recruitment of MAP3K7/TAK1 to IKBKG/NEMO, inducing subsequent activation of IKBKB/IKKB (PubMed:17965022).
In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (By similarity).
The protein kinase activity is dispensable for the NOD1 and NOD2 signaling pathways (By similarity).
Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappa-B activation by NOD2 (By similarity).
Also involved in adaptive immunity: plays a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation (By similarity).
Plays a role in the inactivation of RHOA in response to NGFR signaling (PubMed:26646181).
Catalytic activity
- ATP + L-seryl-[protein] = ADP + H+ + O-phospho-L-seryl-[protein]
Activity regulation
In the inactive state, the helix alphaC is packed against the helical, non-phosphorylated activation segment (AS). Upon activation, helix alphaC is displaced and the phosphorylated AS becomes disordered.
Features
Showing features for binding site, active site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameReceptor-interacting serine/threonine-protein kinase 2
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionP58801
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Peripheral membrane protein
Note: Recruited to the cell membrane by NOD2 following stimulation by bacterial peptidoglycans.
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Mice show a lack of chemokine production induced by bacterial peptidoglycans. RIPK2 deficiency affects cellular signaling and cytokine responses triggered by NOD1 and NOD2 ligands, but not TLR ligands.
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 47 | Abolishes protein-kinase activity. Does not affect ubiquitination by PELI3. | ||||
Sequence: K → A | ||||||
Mutagenesis | 176 | Mimics phosphorylation; does not promote stabilization of RIPK2. | ||||
Sequence: S → E | ||||||
Mutagenesis | 209 | Does not prevent polyubiquitination by PELI3. | ||||
Sequence: K → R |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 26 variants from UniProt as well as other sources including ClinVar and dbSNP.
Chemistry
PTM/Processing
Features
Showing features for chain, modified residue, cross-link.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000086609 | 1-539 | Receptor-interacting serine/threonine-protein kinase 2 | |||
Sequence: MNGDAICSALPPIPYHKLADLHYLSRGASGTVSSARHADWRVRVAVKHLHIHTPLLDSERNDILREAEILHKARFSYILPILGICNEPEFLGIVTEYMPNGSLNELLHRKTEYPDIAWPLRFRILHEIALGVNYLHNMNPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSYKSAPEGGTIIYMPPENYEPGQKSRASVKHDIYSYAVIMWEVLSRKQPFEEVTNPLQIMYSVSQGHRPDTSEENLPFDIPHRGLMISLIQSGWAQNPDERPSFLKCLIELEPVLRTFEDITFLEAVIQLKKAKIQSSSSTIHLCDKKMDLSLNIPANHPPQEESCGSSLLSRNTGSPGPSRSLSAPQDKGFLSGAPQDCSSLKAHHCPGNHSWDGIVSVPPGAAFCDRRASSCSLAVISPFLVEKGSERPPIGIAQQWIQSKREAIVSQMTEACLNQSLDALLSRDLIMKEDYELISTKPTRTSKVRQLLDTSDIQGEEFAKVVVQKLKDNKQLGLQPYPEVPVLSKAPPSNFPQNKSL | ||||||
Modified residue | 168 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 174 | Phosphoserine; alternate | ||||
Sequence: S | ||||||
Modified residue | 176 | Phosphoserine; by autocatalysis | ||||
Sequence: S | ||||||
Modified residue | 178 | Phosphoserine; alternate | ||||
Sequence: S | ||||||
Modified residue | 180 | Phosphoserine | ||||
Sequence: S | ||||||
Cross-link | 209 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 362 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 392 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 411 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 473 | Phosphotyrosine; by autocatalysis | ||||
Sequence: Y | ||||||
Cross-link | 502 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 526 | Phosphoserine | ||||
Sequence: S | ||||||
Cross-link | 537 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 538 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Polyubiquitinated via both 'Lys-63'- and 'Met-1'-linked polyubiquitin following recruitment by NOD1 or NOD2, creating docking sites for downstream effectors, triggering activation of the NF-kappa-B and MAP kinases signaling (PubMed:17947236).
'Lys-63'-linked polyubiquitination by XIAP is essential for NOD2 signaling and promotes recruitment of the LUBAC complex (By similarity).
Also polyubiquitinated with 'Lys-63'-linked chains by PELI3, BIRC2/c-IAP1 and BIRC3/c-IAP2 (PubMed:23892723).
Ubiquitinated on Lys-209 via 'Lys-63'-linked by ITCH (By similarity).
Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to attenuate NOD2-mediated inflammation and tissue damage (PubMed:30405132).
Polyubiquitinated with 'Lys-63'-linked chains in response to Shigella infection, promoting its SQSTM1/p62-dependent autophagic degradation (By similarity).
Undergoes 'Met-1'-linked polyubiquitination; the head-to-tail linear polyubiquitination is mediated by the LUBAC complex in response to NOD2 stimulation 'Met-1'-linked polyubiquitination (By similarity).
'Lys-63'-linked polyubiquitination by XIAP is required for recruimtent of the LUBAC complex and subsequent (By similarity).
Linear polyubiquitination is restricted by FAM105B/otulin, probably to limit NOD2-dependent pro-inflammatory signaling activation of NF-kappa-B (By similarity).
Ubiquitination at Lys-502 by ZNRF4 via 'Lys-48'-linked polyubiquitination promotes RIPK2 degradation by the proteasome; ubiquitination by ZNRF4 takes place during both acute and NOD2 tolerance conditions (By similarity).
'Lys-63'-linked polyubiquitination by XIAP is essential for NOD2 signaling and promotes recruitment of the LUBAC complex (By similarity).
Also polyubiquitinated with 'Lys-63'-linked chains by PELI3, BIRC2/c-IAP1 and BIRC3/c-IAP2 (PubMed:23892723).
Ubiquitinated on Lys-209 via 'Lys-63'-linked by ITCH (By similarity).
Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to attenuate NOD2-mediated inflammation and tissue damage (PubMed:30405132).
Polyubiquitinated with 'Lys-63'-linked chains in response to Shigella infection, promoting its SQSTM1/p62-dependent autophagic degradation (By similarity).
Undergoes 'Met-1'-linked polyubiquitination; the head-to-tail linear polyubiquitination is mediated by the LUBAC complex in response to NOD2 stimulation 'Met-1'-linked polyubiquitination (By similarity).
'Lys-63'-linked polyubiquitination by XIAP is required for recruimtent of the LUBAC complex and subsequent (By similarity).
Linear polyubiquitination is restricted by FAM105B/otulin, probably to limit NOD2-dependent pro-inflammatory signaling activation of NF-kappa-B (By similarity).
Ubiquitination at Lys-502 by ZNRF4 via 'Lys-48'-linked polyubiquitination promotes RIPK2 degradation by the proteasome; ubiquitination by ZNRF4 takes place during both acute and NOD2 tolerance conditions (By similarity).
Autophosphorylated (PubMed:19473975).
Phosphorylated at Ser-176, either via autophosphorylation or by LRRK2, enhancing activity (PubMed:19473975).
Autophosphorylation at Tyr-473 is required for effective NOD2 signaling (By similarity).
Autophosphorylation is however not essential for NOD2 signaling (By similarity).
Phosphorylated at Ser-176, either via autophosphorylation or by LRRK2, enhancing activity (PubMed:19473975).
Autophosphorylation at Tyr-473 is required for effective NOD2 signaling (By similarity).
Autophosphorylation is however not essential for NOD2 signaling (By similarity).
Degraded via selective autophagy following interaction with Irgm1. Irgm1 promotes NOD1/NOD2-RIPK2 RIPosome recruitment to autophagosome membranes. RIPK2 biquitinated via 'Lys-63'-linked chains is then recognized by SQSTM1/p62, leading to the SQSTM1/p62-dependent autophagic degradation of the NOD1/NOD2-RIPK2 RIPosome.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Gene expression databases
Interaction
Subunit
Interacts (via CARD domain) with NOD2 (via CARD domain) (By similarity).
Interacts (via CARD domain) with NOD1 (via CARD domain) (By similarity).
Homooligomer; following interaction with NOD1 or NOD2, homooligomerizes via its CARD domain and forms long filaments named RIPosomes (By similarity).
Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2 (By similarity).
Interacts with ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK (By similarity).
Interacts with MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling pathway (By similarity).
Interacts with IKBKG/NEMO (By similarity).
The polyubiquitinated protein interacts with MAP3K7/TAK1; interaction is indirect and is mediated by TAB2 and TAB3 that bind to polyubiquitin chains attached to RIPK2 (By similarity).
Binds to CFLAR/CLARP and CASP1 via their CARD domains (By similarity).
Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6 (By similarity).
Interacts with NLRP10 (By similarity).
Interacts with CARD9 (PubMed:17187069).
Interacts with INAVA; the interaction takes place upon PRR stimulation (By similarity).
Interacts (via CARD domain) with NGFR (via death domain) (By similarity).
Interacts with Irgm1; promoting RIPK2 degradation (By similarity).
Interacts (via CARD domain) with NOD1 (via CARD domain) (By similarity).
Homooligomer; following interaction with NOD1 or NOD2, homooligomerizes via its CARD domain and forms long filaments named RIPosomes (By similarity).
Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2 (By similarity).
Interacts with ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK (By similarity).
Interacts with MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling pathway (By similarity).
Interacts with IKBKG/NEMO (By similarity).
The polyubiquitinated protein interacts with MAP3K7/TAK1; interaction is indirect and is mediated by TAB2 and TAB3 that bind to polyubiquitin chains attached to RIPK2 (By similarity).
Binds to CFLAR/CLARP and CASP1 via their CARD domains (By similarity).
Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6 (By similarity).
Interacts with NLRP10 (By similarity).
Interacts with CARD9 (PubMed:17187069).
Interacts with INAVA; the interaction takes place upon PRR stimulation (By similarity).
Interacts (via CARD domain) with NGFR (via death domain) (By similarity).
Interacts with Irgm1; promoting RIPK2 degradation (By similarity).
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 18-294 | Protein kinase | ||||
Sequence: LADLHYLSRGASGTVSSARHADWRVRVAVKHLHIHTPLLDSERNDILREAEILHKARFSYILPILGICNEPEFLGIVTEYMPNGSLNELLHRKTEYPDIAWPLRFRILHEIALGVNYLHNMNPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSYKSAPEGGTIIYMPPENYEPGQKSRASVKHDIYSYAVIMWEVLSRKQPFEEVTNPLQIMYSVSQGHRPDTSEENLPFDIPHRGLMISLIQSGWAQNPDERPSFLKCLIELEPVL | ||||||
Region | 65-73 | Helix alphaC | ||||
Sequence: REAEILHKA | ||||||
Region | 167-193 | Activation segment (AS) | ||||
Sequence: LSKWRMMSLSQSRSYKSAPEGGTIIYM | ||||||
Region | 335-368 | Disordered | ||||
Sequence: PANHPPQEESCGSSLLSRNTGSPGPSRSLSAPQD | ||||||
Compositional bias | 337-367 | Polar residues | ||||
Sequence: NHPPQEESCGSSLLSRNTGSPGPSRSLSAPQ | ||||||
Domain | 431-523 | CARD | ||||
Sequence: PIGIAQQWIQSKREAIVSQMTEACLNQSLDALLSRDLIMKEDYELISTKPTRTSKVRQLLDTSDIQGEEFAKVVVQKLKDNKQLGLQPYPEVP | ||||||
Region | 519-539 | Disordered | ||||
Sequence: YPEVPVLSKAPPSNFPQNKSL |
Domain
Contains an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD) that mediates the recruitment of CARD-containing proteins.
Sequence similarities
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length539
- Mass (Da)60,400
- Last updated2002-05-02 v1
- Checksum42951BF97CA15DFA
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
V9GXY4 | V9GXY4_MOUSE | Ripk2 | 315 |
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 337-367 | Polar residues | ||||
Sequence: NHPPQEESCGSSLLSRNTGSPGPSRSLSAPQ |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF461040 EMBL· GenBank· DDBJ | AAL96436.1 EMBL· GenBank· DDBJ | mRNA | ||
BC069878 EMBL· GenBank· DDBJ | AAH69878.1 EMBL· GenBank· DDBJ | mRNA |