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Protein

Receptor-interacting serine/threonine-protein kinase 2

Gene

Ripk2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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.1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei47ATPPROSITE-ProRule annotation1
Active sitei146Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi24 – 32ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processAdaptive immunity, Apoptosis, Immunity, Innate immunity
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-168638 NOD1/2 Signaling Pathway
R-MMU-202424 Downstream TCR signaling
R-MMU-209543 p75NTR recruits signalling complexes
R-MMU-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
R-MMU-450302 activated TAK1 mediates p38 MAPK activation
R-MMU-450321 JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-MMU-5689896 Ovarian tumor domain proteases
R-MMU-9020702 Interleukin-1 signaling

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:Ripk2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:1891456 Ripk2

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Disruption phenotypei

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.2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000866091 – 539Receptor-interacting serine/threonine-protein kinase 2Add BLAST539

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei168PhosphoserineBy similarity1
Modified residuei176Phosphoserine; by autocatalysisBy similarity1
Cross-linki209Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei362PhosphoserineBy similarity1
Modified residuei392PhosphoserineBy similarity1
Modified residuei411PhosphoserineCombined sources1
Modified residuei473Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei526PhosphoserineBy similarity1
Modified residuei538PhosphoserineBy similarity1

Post-translational modificationi

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

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP58801
PaxDbiP58801
PeptideAtlasiP58801
PRIDEiP58801

PTM databases

iPTMnetiP58801
PhosphoSitePlusiP58801

Expressioni

Gene expression databases

BgeeiENSMUSG00000041135 Expressed in 166 organ(s), highest expression level in oocyte
ExpressionAtlasiP58801 baseline and differential
GenevisibleiP58801 MM

Interactioni

Subunit structurei

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. Interacts with INAVA; the interaction takes place upon PRR stimulation (By similarity).By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

BioGridi228697, 7 interactors
CORUMiP58801
IntActiP58801, 2 interactors
STRINGi10090.ENSMUSP00000038833

Structurei

3D structure databases

ProteinModelPortaliP58801
SMRiP58801
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini18 – 294Protein kinasePROSITE-ProRule annotationAdd BLAST277
Domaini431 – 523CARDPROSITE-ProRule annotationAdd BLAST93

Domaini

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

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0192 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00550000074536
HOGENOMiHOG000136856
HOVERGENiHBG054242
InParanoidiP58801
KOiK08846
OMAiQWIQSKR
OrthoDBiEOG091G0505
PhylomeDBiP58801
TreeFamiTF106506

Family and domain databases

InterProiView protein in InterPro
IPR001315 CARD
IPR011029 DEATH-like_dom_sf
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017322 Rcpt-int_Ser/Thr_kinase-2
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00619 CARD, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PIRSFiPIRSF037921 STPK_RIP2, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF47986 SSF47986, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50209 CARD, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

P58801-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MNGDAICSAL PPIPYHKLAD LHYLSRGASG TVSSARHADW RVRVAVKHLH
60 70 80 90 100
IHTPLLDSER NDILREAEIL HKARFSYILP ILGICNEPEF LGIVTEYMPN
110 120 130 140 150
GSLNELLHRK TEYPDIAWPL RFRILHEIAL GVNYLHNMNP PLLHHDLKTQ
160 170 180 190 200
NILLDNEFHV KIADFGLSKW RMMSLSQSRS YKSAPEGGTI IYMPPENYEP
210 220 230 240 250
GQKSRASVKH DIYSYAVIMW EVLSRKQPFE EVTNPLQIMY SVSQGHRPDT
260 270 280 290 300
SEENLPFDIP HRGLMISLIQ SGWAQNPDER PSFLKCLIEL EPVLRTFEDI
310 320 330 340 350
TFLEAVIQLK KAKIQSSSST IHLCDKKMDL SLNIPANHPP QEESCGSSLL
360 370 380 390 400
SRNTGSPGPS RSLSAPQDKG FLSGAPQDCS SLKAHHCPGN HSWDGIVSVP
410 420 430 440 450
PGAAFCDRRA SSCSLAVISP FLVEKGSERP PIGIAQQWIQ SKREAIVSQM
460 470 480 490 500
TEACLNQSLD ALLSRDLIMK EDYELISTKP TRTSKVRQLL DTSDIQGEEF
510 520 530
AKVVVQKLKD NKQLGLQPYP EVPVLSKAPP SNFPQNKSL
Length:539
Mass (Da):60,400
Last modified:May 2, 2002 - v1
Checksum:i42951BF97CA15DFA
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
V9GXY4V9GXY4_MOUSE
Receptor-interacting serine/threoni...
Ripk2
315Annotation score:

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF461040 mRNA Translation: AAL96436.1
BC069878 mRNA Translation: AAH69878.1
CCDSiCCDS17988.1
RefSeqiNP_620402.1, NM_138952.4
UniGeneiMm.112765

Genome annotation databases

EnsembliENSMUST00000037035; ENSMUSP00000038833; ENSMUSG00000041135
GeneIDi192656
KEGGimmu:192656
UCSCiuc008sbr.1 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF461040 mRNA Translation: AAL96436.1
BC069878 mRNA Translation: AAH69878.1
CCDSiCCDS17988.1
RefSeqiNP_620402.1, NM_138952.4
UniGeneiMm.112765

3D structure databases

ProteinModelPortaliP58801
SMRiP58801
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi228697, 7 interactors
CORUMiP58801
IntActiP58801, 2 interactors
STRINGi10090.ENSMUSP00000038833

PTM databases

iPTMnetiP58801
PhosphoSitePlusiP58801

Proteomic databases

EPDiP58801
PaxDbiP58801
PeptideAtlasiP58801
PRIDEiP58801

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000037035; ENSMUSP00000038833; ENSMUSG00000041135
GeneIDi192656
KEGGimmu:192656
UCSCiuc008sbr.1 mouse

Organism-specific databases

CTDi8767
MGIiMGI:1891456 Ripk2

Phylogenomic databases

eggNOGiKOG0192 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00550000074536
HOGENOMiHOG000136856
HOVERGENiHBG054242
InParanoidiP58801
KOiK08846
OMAiQWIQSKR
OrthoDBiEOG091G0505
PhylomeDBiP58801
TreeFamiTF106506

Enzyme and pathway databases

ReactomeiR-MMU-168638 NOD1/2 Signaling Pathway
R-MMU-202424 Downstream TCR signaling
R-MMU-209543 p75NTR recruits signalling complexes
R-MMU-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
R-MMU-450302 activated TAK1 mediates p38 MAPK activation
R-MMU-450321 JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-MMU-5689896 Ovarian tumor domain proteases
R-MMU-9020702 Interleukin-1 signaling

Miscellaneous databases

PROiPR:P58801
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000041135 Expressed in 166 organ(s), highest expression level in oocyte
ExpressionAtlasiP58801 baseline and differential
GenevisibleiP58801 MM

Family and domain databases

InterProiView protein in InterPro
IPR001315 CARD
IPR011029 DEATH-like_dom_sf
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017322 Rcpt-int_Ser/Thr_kinase-2
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00619 CARD, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PIRSFiPIRSF037921 STPK_RIP2, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF47986 SSF47986, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50209 CARD, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiRIPK2_MOUSE
AccessioniPrimary (citable) accession number: P58801
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: May 2, 2002
Last modified: September 12, 2018
This is version 163 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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