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P58801 (RIPK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 124. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Receptor-interacting serine/threonine-protein kinase 2

EC=2.7.11.1
Alternative name(s):
Tyrosine-protein kinase RIPK2
EC=2.7.10.2
Gene names
Name:Ripk2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length539 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Once recruited, autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is release 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. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation. Ref.5

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

Subunit structure

Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2. Interacts with ARHGEF2. Binds to CFLAR/CLARP and CASP1 via their CARD domains. Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6. May be a component of both the TNFRSF1A and TNRFSF5/CD40 receptor complex. Interacts with NOD1. Interacts (via CARD domain) with NOD2 (via CARD domain). Interacts with MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling pathway. Interacts with IKBKG/NEMO. The polyubiquitinated protein interacts with MAP3K7/TAK1. Interacts with XIAP/BIRC4. Interacts with NLRP10 By similarity. Interacts with CARD9. Ref.4

Subcellular location

Cytoplasm Probable.

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 By similarity.

Post-translational modification

Autophosphorylated. Autophosphorylation at Tyr-473 is necessary for effective NOD2 signaling.

Ubiquitinated on Lys-209; undergoes 'Lys-63'-linked polyubiquitination catalyzed by ITCH. Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B. Also undergoes 'Met-1'-linked polyubiquitination; the head-to-tail linear polyubiquitination is mediated by the LUBAC complex in response to NOD2 stimulation. Linear polyubiquitination is restricted by FAM105B/otulin, probably to limit NOD2-dependent proinflammatory signaling activation of NF-kappa-B By similarity.

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. Ref.3 Ref.5

Sequence similarities

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

Contains 1 CARD domain.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processAdaptive immunity
Apoptosis
Immunity
Innate immunity
   Cellular componentCytoplasm
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processI-kappaB kinase/NF-kappaB signaling

Inferred from mutant phenotype Ref.5. Source: UniProtKB

T cell proliferation

Inferred from mutant phenotype PubMed 14638696. Source: MGI

T cell receptor signaling pathway

Inferred from mutant phenotype Ref.5. Source: UniProtKB

adaptive immune response

Inferred from mutant phenotype Ref.5. Source: UniProtKB

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

cellular response to lipopolysaccharide

Inferred from mutant phenotype Ref.1PubMed 11894098. Source: MGI

cellular response to lipoteichoic acid

Inferred from mutant phenotype PubMed 11894098. Source: MGI

cellular response to muramyl dipeptide

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to peptidoglycan

Inferred from mutant phenotype PubMed 11894098. Source: MGI

defense response to Gram-positive bacterium

Inferred from mutant phenotype Ref.1PubMed 11894098PubMed 18261938. Source: MGI

innate immune response

Inferred from mutant phenotype Ref.5. Source: UniProtKB

lipopolysaccharide-mediated signaling pathway

Inferred from mutant phenotype PubMed 11894098. Source: MGI

nucleotide-binding oligomerization domain containing 1 signaling pathway

Inferred from mutant phenotype PubMed 11894098. Source: MGI

nucleotide-binding oligomerization domain containing 2 signaling pathway

Inferred from mutant phenotype PubMed 11894098. Source: MGI

positive regulation of ERK1 and ERK2 cascade

Inferred from direct assay PubMed 18261938. Source: MGI

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from mutant phenotype Ref.1PubMed 11894098PubMed 18261938. Source: MGI

positive regulation of JNK cascade

Inferred from mutant phenotype Ref.1PubMed 11894098PubMed 18261938. Source: MGI

positive regulation of NF-kappaB transcription factor activity

Inferred from mutant phenotype PubMed 21887730. Source: UniProtKB

positive regulation of T-helper 1 cell differentiation

Inferred from mutant phenotype Ref.1. Source: MGI

positive regulation of T-helper 1 type immune response

Inferred from mutant phenotype Ref.1. Source: MGI

positive regulation of alpha-beta T cell proliferation

Inferred from mutant phenotype Ref.1PubMed 11894098. Source: MGI

positive regulation of apoptotic process

Inferred from direct assay PubMed 14663141. Source: MGI

positive regulation of chemokine production

Inferred from mutant phenotype PubMed 11894098. Source: MGI

positive regulation of cytokine-mediated signaling pathway

Inferred from mutant phenotype Ref.1. Source: MGI

positive regulation of immature T cell proliferation

Inferred from mutant phenotype PubMed 11894098. Source: MGI

positive regulation of interferon-gamma production

Inferred from mutant phenotype Ref.1PubMed 11894098. Source: MGI

positive regulation of interleukin-2 production

Inferred from mutant phenotype PubMed 11894098. Source: MGI

positive regulation of interleukin-6 production

Inferred from mutant phenotype PubMed 21887730. Source: UniProtKB

positive regulation of peptidyl-serine phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of peptidyl-threonine phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of peptidyl-tyrosine phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of protein ubiquitination

Inferred from electronic annotation. Source: Ensembl

positive regulation of stress-activated MAPK cascade

Inferred from mutant phenotype Ref.1PubMed 11894098PubMed 18261938. Source: MGI

positive regulation of tumor necrosis factor production

Inferred from mutant phenotype PubMed 21887730. Source: UniProtKB

response to exogenous dsRNA

Inferred from mutant phenotype PubMed 11894098. Source: MGI

response to interleukin-1

Inferred from mutant phenotype PubMed 11894098. Source: MGI

response to interleukin-12

Inferred from mutant phenotype Ref.1PubMed 11894098. Source: MGI

response to interleukin-18

Inferred from mutant phenotype Ref.1PubMed 11894098. Source: MGI

toll-like receptor 2 signaling pathway

Inferred from electronic annotation. Source: Ensembl

toll-like receptor 4 signaling pathway

Inferred from mutant phenotype PubMed 11894098. Source: MGI

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

cytoskeleton

Inferred from sequence or structural similarity. Source: UniProtKB

cytosol

Traceable author statement. Source: Reactome

protein complex

Inferred from sequence or structural similarity. Source: UniProtKB

vesicle

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

non-membrane spanning protein tyrosine kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

protein serine/threonine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 539539Receptor-interacting serine/threonine-protein kinase 2
PRO_0000086609

Regions

Domain18 – 294277Protein kinase
Domain431 – 52393CARD
Nucleotide binding24 – 329ATP By similarity

Sites

Active site1461Proton acceptor By similarity
Binding site471ATP By similarity

Amino acid modifications

Modified residue1681Phosphoserine By similarity
Modified residue1761Phosphoserine; by autocatalysis By similarity
Modified residue3621Phosphoserine By similarity
Modified residue3921Phosphoserine By similarity
Modified residue4731Phosphotyrosine; by autocatalysis By similarity
Modified residue5261Phosphoserine By similarity
Modified residue5381Phosphoserine By similarity
Cross-link209Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Sequences

Sequence LengthMass (Da)Tools
P58801 [UniParc].

Last modified May 2, 2002. Version 1.
Checksum: 42951BF97CA15DFA

FASTA53960,400
        10         20         30         40         50         60 
MNGDAICSAL PPIPYHKLAD LHYLSRGASG TVSSARHADW RVRVAVKHLH IHTPLLDSER 

        70         80         90        100        110        120 
NDILREAEIL HKARFSYILP ILGICNEPEF LGIVTEYMPN GSLNELLHRK TEYPDIAWPL 

       130        140        150        160        170        180 
RFRILHEIAL GVNYLHNMNP PLLHHDLKTQ NILLDNEFHV KIADFGLSKW RMMSLSQSRS 

       190        200        210        220        230        240 
YKSAPEGGTI IYMPPENYEP GQKSRASVKH DIYSYAVIMW EVLSRKQPFE EVTNPLQIMY 

       250        260        270        280        290        300 
SVSQGHRPDT SEENLPFDIP HRGLMISLIQ SGWAQNPDER PSFLKCLIEL EPVLRTFEDI 

       310        320        330        340        350        360 
TFLEAVIQLK KAKIQSSSST IHLCDKKMDL SLNIPANHPP QEESCGSSLL SRNTGSPGPS 

       370        380        390        400        410        420 
RSLSAPQDKG FLSGAPQDCS SLKAHHCPGN HSWDGIVSVP PGAAFCDRRA SSCSLAVISP 

       430        440        450        460        470        480 
FLVEKGSERP PIGIAQQWIQ SKREAIVSQM TEACLNQSLD ALLSRDLIMK EDYELISTKP 

       490        500        510        520        530 
TRTSKVRQLL DTSDIQGEEF AKVVVQKLKD NKQLGLQPYP EVPVLSKAPP SNFPQNKSL 

« Hide

References

« Hide 'large scale' references
[1]"Involvement of receptor-interacting protein 2 in innate and adaptive immune responses."
Chin A.I., Dempsey P.W., Bruhn K., Miller J.F., Xu Y., Cheng G.
Nature 416:190-194(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: C57BL/6.
[2]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: 129.
Tissue: Mammary gland.
[3]"RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs."
Park J.H., Kim Y.G., McDonald C., Kanneganti T.D., Hasegawa M., Body-Malapel M., Inohara N., Nunez G.
J. Immunol. 178:2380-2386(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[4]"The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens."
Hsu Y.M., Zhang Y., You Y., Wang D., Li H., Duramad O., Qin X.F., Dong C., Lin X.
Nat. Immunol. 8:198-205(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CARD9.
[5]"Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands."
Magalhaes J.G., Lee J., Geddes K., Rubino S., Philpott D.J., Girardin S.E.
Eur. J. Immunol. 41:1445-1455(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF461040 mRNA. Translation: AAL96436.1.
BC069878 mRNA. Translation: AAH69878.1.
RefSeqNP_620402.1. NM_138952.3.
UniGeneMm.112765.

3D structure databases

ProteinModelPortalP58801.
SMRP58801. Positions 9-316.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid228697. 5 interactions.

PTM databases

PhosphoSiteP58801.

Proteomic databases

PaxDbP58801.
PRIDEP58801.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000037035; ENSMUSP00000038833; ENSMUSG00000041135.
GeneID192656.
KEGGmmu:192656.
UCSCuc008sbr.1. mouse.

Organism-specific databases

CTD8767.
MGIMGI:1891456. Ripk2.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000136856.
HOVERGENHBG054242.
InParanoidP58801.
KOK08846.
OMAPDVAWPL.
OrthoDBEOG78H3SS.
PhylomeDBP58801.
TreeFamTF106506.

Enzyme and pathway databases

ReactomeREACT_98458. Immune System.

Gene expression databases

ArrayExpressP58801.
BgeeP58801.
GenevestigatorP58801.

Family and domain databases

Gene3D1.10.533.10. 1 hit.
InterProIPR001315. CARD.
IPR011029. DEATH-like_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017322. Rcpt-int_Ser/Thr_kinase-2.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00619. CARD. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFPIRSF037921. STPK_RIP2. 1 hit.
SMARTSM00114. CARD. 1 hit.
[Graphical view]
SUPFAMSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS50209. CARD. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio371321.
PROP58801.
SOURCESearch...

Entry information

Entry nameRIPK2_MOUSE
AccessionPrimary (citable) accession number: P58801
Entry history
Integrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: May 2, 2002
Last modified: April 16, 2014
This is version 124 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot