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P58801

- RIPK2_MOUSE

UniProt

P58801 - RIPK2_MOUSE

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Protein

Receptor-interacting serine/threonine-protein kinase 2

Gene

Ripk2

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- 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)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei47 – 471ATPPROSITE-ProRule annotation
Active sitei146 – 1461Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi24 – 329ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. non-membrane spanning protein tyrosine kinase activity Source: UniProtKB-EC
  3. protein serine/threonine kinase activity Source: UniProtKB-KW

GO - Biological processi

  1. adaptive immune response Source: UniProtKB
  2. apoptotic process Source: UniProtKB-KW
  3. cellular response to lipopolysaccharide Source: MGI
  4. cellular response to lipoteichoic acid Source: MGI
  5. cellular response to muramyl dipeptide Source: UniProtKB
  6. cellular response to peptidoglycan Source: MGI
  7. defense response to Gram-positive bacterium Source: MGI
  8. I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
  9. innate immune response Source: UniProtKB
  10. lipopolysaccharide-mediated signaling pathway Source: MGI
  11. nucleotide-binding oligomerization domain containing 1 signaling pathway Source: MGI
  12. nucleotide-binding oligomerization domain containing 2 signaling pathway Source: MGI
  13. positive regulation of alpha-beta T cell proliferation Source: MGI
  14. positive regulation of apoptotic process Source: MGI
  15. positive regulation of chemokine production Source: MGI
  16. positive regulation of cytokine-mediated signaling pathway Source: MGI
  17. positive regulation of ERK1 and ERK2 cascade Source: MGI
  18. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
  19. positive regulation of immature T cell proliferation Source: MGI
  20. positive regulation of interferon-gamma production Source: MGI
  21. positive regulation of interleukin-2 production Source: MGI
  22. positive regulation of interleukin-6 production Source: UniProtKB
  23. positive regulation of JNK cascade Source: MGI
  24. positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  25. positive regulation of peptidyl-serine phosphorylation Source: UniProtKB
  26. positive regulation of peptidyl-threonine phosphorylation Source: UniProtKB
  27. positive regulation of peptidyl-tyrosine phosphorylation Source: UniProtKB
  28. positive regulation of protein ubiquitination Source: Ensembl
  29. positive regulation of stress-activated MAPK cascade Source: MGI
  30. positive regulation of T-helper 1 cell differentiation Source: MGI
  31. positive regulation of T-helper 1 type immune response Source: MGI
  32. positive regulation of tumor necrosis factor production Source: UniProtKB
  33. response to exogenous dsRNA Source: MGI
  34. response to interleukin-1 Source: MGI
  35. response to interleukin-12 Source: MGI
  36. response to interleukin-18 Source: MGI
  37. T cell proliferation Source: MGI
  38. T cell receptor signaling pathway Source: UniProtKB
  39. toll-like receptor 2 signaling pathway Source: Ensembl
  40. toll-like receptor 4 signaling pathway Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Adaptive immunity, Apoptosis, Immunity, Innate immunity

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiREACT_204812. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
REACT_211125. NOD1/2 Signaling Pathway.
REACT_214670. p75NTR recruits signalling complexes.
REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
REACT_224208. Interleukin-1 signaling.
REACT_225145. Downstream TCR signaling.
REACT_237946. activated TAK1 mediates p38 MAPK activation.

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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 4

Organism-specific databases

MGIiMGI:1891456. Ripk2.

Subcellular locationi

Cytoplasm Curated

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB
  2. cytoskeleton Source: UniProtKB
  3. cytosol Source: Reactome
  4. protein complex Source: UniProtKB
  5. vesicle Source: UniProtKB
Complete GO annotation...

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)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 539539Receptor-interacting serine/threonine-protein kinase 2PRO_0000086609Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei168 – 1681PhosphoserineBy similarity
Modified residuei176 – 1761Phosphoserine; by autocatalysisBy similarity
Cross-linki209 – 209Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei362 – 3621PhosphoserineBy similarity
Modified residuei392 – 3921PhosphoserineBy similarity
Modified residuei473 – 4731Phosphotyrosine; by autocatalysisBy similarity
Modified residuei526 – 5261PhosphoserineBy similarity
Modified residuei538 – 5381PhosphoserineBy similarity

Post-translational modificationi

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).By similarity

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiP58801.
PaxDbiP58801.
PRIDEiP58801.

PTM databases

PhosphoSiteiP58801.

Expressioni

Gene expression databases

BgeeiP58801.
ExpressionAtlasiP58801. baseline and differential.
GenevestigatoriP58801.

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.By similarity1 Publication

Protein-protein interaction databases

BioGridi228697. 5 interactions.

Structurei

3D structure databases

ProteinModelPortaliP58801.
SMRiP58801. Positions 9-316.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini18 – 294277Protein kinasePROSITE-ProRule annotationAdd
BLAST
Domaini431 – 52393CARDPROSITE-ProRule annotationAdd
BLAST

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

Contains 1 CARD domain.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000136856.
HOVERGENiHBG054242.
InParanoidiP58801.
KOiK08846.
OMAiYPDVAWP.
OrthoDBiEOG78H3SS.
PhylomeDBiP58801.
TreeFamiTF106506.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
InterProiIPR001315. 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]
PfamiPF00619. CARD. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFiPIRSF037921. STPK_RIP2. 1 hit.
SMARTiSM00114. CARD. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50209. CARD. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

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_138952.3.
UniGeneiMm.112765.

Genome annotation databases

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

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF461040 mRNA. Translation: AAL96436.1 .
BC069878 mRNA. Translation: AAH69878.1 .
CCDSi CCDS17988.1.
RefSeqi NP_620402.1. NM_138952.3.
UniGenei Mm.112765.

3D structure databases

ProteinModelPortali P58801.
SMRi P58801. Positions 9-316.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 228697. 5 interactions.

PTM databases

PhosphoSitei P58801.

Proteomic databases

MaxQBi P58801.
PaxDbi P58801.
PRIDEi P58801.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000037035 ; ENSMUSP00000038833 ; ENSMUSG00000041135 .
GeneIDi 192656.
KEGGi mmu:192656.
UCSCi uc008sbr.1. mouse.

Organism-specific databases

CTDi 8767.
MGIi MGI:1891456. Ripk2.

Phylogenomic databases

eggNOGi COG0515.
HOGENOMi HOG000136856.
HOVERGENi HBG054242.
InParanoidi P58801.
KOi K08846.
OMAi YPDVAWP.
OrthoDBi EOG78H3SS.
PhylomeDBi P58801.
TreeFami TF106506.

Enzyme and pathway databases

Reactomei REACT_204812. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
REACT_211125. NOD1/2 Signaling Pathway.
REACT_214670. p75NTR recruits signalling complexes.
REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
REACT_224208. Interleukin-1 signaling.
REACT_225145. Downstream TCR signaling.
REACT_237946. activated TAK1 mediates p38 MAPK activation.

Miscellaneous databases

NextBioi 371321.
PROi P58801.
SOURCEi Search...

Gene expression databases

Bgeei P58801.
ExpressionAtlasi P58801. baseline and differential.
Genevestigatori P58801.

Family and domain databases

Gene3Di 1.10.533.10. 1 hit.
InterProi IPR001315. 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 ]
Pfami PF00619. CARD. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view ]
PIRSFi PIRSF037921. STPK_RIP2. 1 hit.
SMARTi SM00114. CARD. 1 hit.
[Graphical view ]
SUPFAMi SSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEi PS50209. CARD. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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.

Entry informationi

Entry nameiRIPK2_MOUSE
AccessioniPrimary (citable) accession number: P58801
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: May 2, 2002
Last modified: November 26, 2014
This is version 130 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3