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Protein

Receptor-interacting serine/threonine-protein kinase 2

Gene

RIPK2

Organism
Homo sapiens (Human)
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. Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Once recruited, RIPK2 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 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. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation.5 Publications

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 sitei47ATP1
Active sitei146Proton acceptor1

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

BRENDAi2.7.10.2 2681
ReactomeiR-HSA-168638 NOD1/2 Signaling Pathway
R-HSA-202424 Downstream TCR signaling
R-HSA-209543 p75NTR recruits signalling complexes
R-HSA-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
R-HSA-450302 activated TAK1 mediates p38 MAPK activation
R-HSA-450321 JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-5689896 Ovarian tumor domain proteases
R-HSA-9020702 Interleukin-1 signaling
SignaLinkiO43353
SIGNORiO43353

Names & Taxonomyi

Protein namesi
Recommended name:
Receptor-interacting serine/threonine-protein kinase 2 (EC:2.7.11.1)
Alternative name(s):
CARD-containing interleukin-1 beta-converting enzyme-associated kinase
Short name:
CARD-containing IL-1 beta ICE-kinase
RIP-like-interacting CLARP kinase
Receptor-interacting protein 2
Short name:
RIP-2
Tyrosine-protein kinase RIPK2 (EC:2.7.10.2)
Gene namesi
Name:RIPK2
Synonyms:CARDIAK, RICK, RIP2
ORF Names:UNQ277/PRO314/PRO34092
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 8

Organism-specific databases

EuPathDBiHostDB:ENSG00000104312.7
HGNCiHGNC:10020 RIPK2
MIMi603455 gene
neXtProtiNX_O43353

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

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi47K → A: Abolishes kinase activity. 2 Publications1
Mutagenesisi47K → M: Reduces FAS-mediated apoptosis. 2 Publications1
Mutagenesisi146D → N: Abolishes kinase activity. 1 Publication1
Mutagenesisi209K → R: Complete loss of polyubiquitination. 1 Publication1
Mutagenesisi381Y → A: Prevents phosphorylation. Reduces serine and threonine phosphorylation of ARHGEF2. 1
Mutagenesisi444R → E: Abolishes interaction with NOD1. 1 Publication1
Mutagenesisi474Y → F: Decreases interaction with NOD2. 1 Publication1
Mutagenesisi483R → E: Abolishes interaction with NOD1. 1 Publication1
Mutagenesisi488R → E: Abolishes interaction with NOD1. 1 Publication1

Organism-specific databases

DisGeNETi8767
OpenTargetsiENSG00000104312
PharmGKBiPA34395

Chemistry databases

ChEMBLiCHEMBL5014
GuidetoPHARMACOLOGYi2190

Polymorphism and mutation databases

BioMutaiRIPK2

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000866081 – 540Receptor-interacting serine/threonine-protein kinase 2Add BLAST540

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei168PhosphoserineCombined sources1
Modified residuei176Phosphoserine; by autocatalysis1 Publication1
Cross-linki209Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei363PhosphoserineCombined sources1
Modified residuei381Phosphotyrosine; by CSK1 Publication1
Modified residuei393PhosphoserineCombined sources1
Modified residuei474Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei527PhosphoserineCombined sources1
Modified residuei529PhosphoserineCombined sources1
Modified residuei531PhosphoserineCombined sources1
Modified residuei539PhosphoserineCombined sources1

Post-translational modificationi

Autophosphorylated. Autophosphorylation at Tyr-474 is necessary for effective NOD2 signaling. Phosphorylated. Phosphorylation at Tyr-381 by Src kinase CSK occurs in a ARHGEF2-dependent manner and is required for NOD2-dependent innate immune activation.3 Publications
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.5 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO43353
MaxQBiO43353
PaxDbiO43353
PeptideAtlasiO43353
PRIDEiO43353
ProteomicsDBi48908
48909 [O43353-2]

PTM databases

iPTMnetiO43353
PhosphoSitePlusiO43353

Expressioni

Tissue specificityi

Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node.

Gene expression databases

BgeeiENSG00000104312 Expressed in 202 organ(s), highest expression level in smooth muscle tissue
CleanExiHS_RIPK2
ExpressionAtlasiO43353 baseline and differential
GenevisibleiO43353 HS

Organism-specific databases

HPAiHPA015273
HPA016499

Interactioni

Subunit structurei

Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2. Interacts with ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK. 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) (PubMed:19592251, PubMed:21887730, PubMed:27812135). 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. Interacts with CARD9. Interacts with INAVA; the interaction takes place upon PRR stimulation (PubMed:28436939).9 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi114300, 47 interactors
DIPiDIP-27518N
IntActiO43353, 15 interactors
MINTiO43353
STRINGi9606.ENSP00000220751

Chemistry databases

BindingDBiO43353

Structurei

Secondary structure

1540
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliO43353
SMRiO43353
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini18 – 294Protein kinasePROSITE-ProRule annotationAdd BLAST277
Domaini432 – 524CARDPROSITE-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.

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0192 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00550000074536
HOGENOMiHOG000136856
HOVERGENiHBG054242
InParanoidiO43353
KOiK08846
OMAiPFEEVIN
OrthoDBiEOG091G0505
PhylomeDBiO43353
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

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: O43353-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MNGEAICSAL PTIPYHKLAD LRYLSRGASG TVSSARHADW RVQVAVKHLH
60 70 80 90 100
IHTPLLDSER KDVLREAEIL HKARFSYILP ILGICNEPEF LGIVTEYMPN
110 120 130 140 150
GSLNELLHRK TEYPDVAWPL RFRILHEIAL GVNYLHNMTP PLLHHDLKTQ
160 170 180 190 200
NILLDNEFHV KIADFGLSKW RMMSLSQSRS SKSAPEGGTI IYMPPENYEP
210 220 230 240 250
GQKSRASIKH DIYSYAVITW EVLSRKQPFE DVTNPLQIMY SVSQGHRPVI
260 270 280 290 300
NEESLPYDIP HRARMISLIE SGWAQNPDER PSFLKCLIEL EPVLRTFEEI
310 320 330 340 350
TFLEAVIQLK KTKLQSVSSA IHLCDKKKME LSLNIPVNHG PQEESCGSSQ
360 370 380 390 400
LHENSGSPET SRSLPAPQDN DFLSRKAQDC YFMKLHHCPG NHSWDSTISG
410 420 430 440 450
SQRAAFCDHK TTPCSSAIIN PLSTAGNSER LQPGIAQQWI QSKREDIVNQ
460 470 480 490 500
MTEACLNQSL DALLSRDLIM KEDYELVSTK PTRTSKVRQL LDTTDIQGEE
510 520 530 540
FAKVIVQKLK DNKQMGLQPY PEILVVSRSP SLNLLQNKSM
Length:540
Mass (Da):61,195
Last modified:November 1, 1998 - v2
Checksum:i575A692239505792
GO
Isoform 2 (identifier: O43353-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-137: Missing.

Show »
Length:403
Mass (Da):45,582
Checksum:i9F0DE53A01B25EF5
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
E7ERW9E7ERW9_HUMAN
Receptor-interacting serine-threoni...
RIPK2
68Annotation score:
E5RGK6E5RGK6_HUMAN
Receptor-interacting serine/threoni...
RIPK2
70Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti271S → G in BAH13484 (PubMed:14702039).Curated1
Sequence conflicti514Q → R in BAH13484 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_041045259I → T1 PublicationCorresponds to variant dbSNP:rs2230801Ensembl.1
Natural variantiVAR_041046268L → V1 PublicationCorresponds to variant dbSNP:rs35004667Ensembl.1
Natural variantiVAR_041047313K → N1 PublicationCorresponds to variant dbSNP:rs35395048Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0132661 – 137Missing in isoform 2. 2 PublicationsAdd BLAST137

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF027706 mRNA Translation: AAC34970.1
AF078530 mRNA Translation: AAC27722.1
AF064824 mRNA Translation: AAC25668.1
AY358813 mRNA Translation: AAQ89172.1
AY358814 mRNA Translation: AAQ89173.1
AK301448 mRNA Translation: BAH13484.1
AC004003 Genomic DNA Translation: AAC24561.1
AF117829 Genomic DNA No translation available.
BC004553 mRNA Translation: AAH04553.1
CCDSiCCDS6247.1 [O43353-1]
RefSeqiNP_003812.1, NM_003821.5 [O43353-1]
XP_005251149.1, XM_005251092.3 [O43353-2]
UniGeneiHs.103755

Genome annotation databases

EnsembliENST00000220751; ENSP00000220751; ENSG00000104312 [O43353-1]
GeneIDi8767
KEGGihsa:8767
UCSCiuc003yee.4 human [O43353-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF027706 mRNA Translation: AAC34970.1
AF078530 mRNA Translation: AAC27722.1
AF064824 mRNA Translation: AAC25668.1
AY358813 mRNA Translation: AAQ89172.1
AY358814 mRNA Translation: AAQ89173.1
AK301448 mRNA Translation: BAH13484.1
AC004003 Genomic DNA Translation: AAC24561.1
AF117829 Genomic DNA No translation available.
BC004553 mRNA Translation: AAH04553.1
CCDSiCCDS6247.1 [O43353-1]
RefSeqiNP_003812.1, NM_003821.5 [O43353-1]
XP_005251149.1, XM_005251092.3 [O43353-2]
UniGeneiHs.103755

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2N7ZNMR-A434-539[»]
2N83NMR-B434-539[»]
4C8BX-ray2.75A/B8-317[»]
5AR2X-ray2.44A/B1-310[»]
5AR3X-ray3.23A/B1-310[»]
5AR4X-ray2.70A/B1-310[»]
5AR5X-ray2.66A/B1-310[»]
5AR7X-ray2.71A/B1-310[»]
5AR8X-ray2.79A/B1-310[»]
5J79X-ray2.69A/B1-310[»]
5J7BX-ray2.53A/B1-310[»]
5NG0X-ray2.00A/B1-300[»]
5NG2X-ray2.80A/B1-300[»]
5NG3X-ray2.60A/B/C/D1-300[»]
5W5JX-ray2.85A/B2-311[»]
5W5OX-ray2.89A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P2-311[»]
6ES0X-ray2.38A/B3-317[»]
6FU5X-ray3.26A/B3-317[»]
ProteinModelPortaliO43353
SMRiO43353
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114300, 47 interactors
DIPiDIP-27518N
IntActiO43353, 15 interactors
MINTiO43353
STRINGi9606.ENSP00000220751

Chemistry databases

BindingDBiO43353
ChEMBLiCHEMBL5014
GuidetoPHARMACOLOGYi2190

PTM databases

iPTMnetiO43353
PhosphoSitePlusiO43353

Polymorphism and mutation databases

BioMutaiRIPK2

Proteomic databases

EPDiO43353
MaxQBiO43353
PaxDbiO43353
PeptideAtlasiO43353
PRIDEiO43353
ProteomicsDBi48908
48909 [O43353-2]

Protocols and materials databases

DNASUi8767
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000220751; ENSP00000220751; ENSG00000104312 [O43353-1]
GeneIDi8767
KEGGihsa:8767
UCSCiuc003yee.4 human [O43353-1]

Organism-specific databases

CTDi8767
DisGeNETi8767
EuPathDBiHostDB:ENSG00000104312.7
GeneCardsiRIPK2
HGNCiHGNC:10020 RIPK2
HPAiHPA015273
HPA016499
MIMi603455 gene
neXtProtiNX_O43353
OpenTargetsiENSG00000104312
PharmGKBiPA34395
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0192 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00550000074536
HOGENOMiHOG000136856
HOVERGENiHBG054242
InParanoidiO43353
KOiK08846
OMAiPFEEVIN
OrthoDBiEOG091G0505
PhylomeDBiO43353
TreeFamiTF106506

Enzyme and pathway databases

BRENDAi2.7.10.2 2681
ReactomeiR-HSA-168638 NOD1/2 Signaling Pathway
R-HSA-202424 Downstream TCR signaling
R-HSA-209543 p75NTR recruits signalling complexes
R-HSA-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
R-HSA-450302 activated TAK1 mediates p38 MAPK activation
R-HSA-450321 JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-5689896 Ovarian tumor domain proteases
R-HSA-9020702 Interleukin-1 signaling
SignaLinkiO43353
SIGNORiO43353

Miscellaneous databases

ChiTaRSiRIPK2 human
GeneWikiiRIPK2
GenomeRNAii8767
PROiPR:O43353
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000104312 Expressed in 202 organ(s), highest expression level in smooth muscle tissue
CleanExiHS_RIPK2
ExpressionAtlasiO43353 baseline and differential
GenevisibleiO43353 HS

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_HUMAN
AccessioniPrimary (citable) accession number: O43353
Secondary accession number(s): B7Z748, Q6UWF0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: November 1, 1998
Last modified: November 7, 2018
This is version 201 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human chromosome 8
    Human chromosome 8: entries, gene names and cross-references to MIM
  7. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
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