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P58801

- RIPK2_MOUSE

UniProt

P58801 - RIPK2_MOUSE

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
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    • History
      Entry version 128 (01 Oct 2014)
      Sequence version 1 (02 May 2002)
      Previous versions | rss
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    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

    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.

    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

    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

    ArrayExpressiP58801.
    BgeeiP58801.
    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

    MNGDAICSAL PPIPYHKLAD LHYLSRGASG TVSSARHADW RVRVAVKHLH    50
    IHTPLLDSER NDILREAEIL HKARFSYILP ILGICNEPEF LGIVTEYMPN 100
    GSLNELLHRK TEYPDIAWPL RFRILHEIAL GVNYLHNMNP PLLHHDLKTQ 150
    NILLDNEFHV KIADFGLSKW RMMSLSQSRS YKSAPEGGTI IYMPPENYEP 200
    GQKSRASVKH DIYSYAVIMW EVLSRKQPFE EVTNPLQIMY SVSQGHRPDT 250
    SEENLPFDIP HRGLMISLIQ SGWAQNPDER PSFLKCLIEL EPVLRTFEDI 300
    TFLEAVIQLK KAKIQSSSST IHLCDKKMDL SLNIPANHPP QEESCGSSLL 350
    SRNTGSPGPS RSLSAPQDKG FLSGAPQDCS SLKAHHCPGN HSWDGIVSVP 400
    PGAAFCDRRA SSCSLAVISP FLVEKGSERP PIGIAQQWIQ SKREAIVSQM 450
    TEACLNQSLD ALLSRDLIMK EDYELISTKP TRTSKVRQLL DTSDIQGEEF 500
    AKVVVQKLKD NKQLGLQPYP EVPVLSKAPP SNFPQNKSL 539
    Length:539
    Mass (Da):60,400
    Last modified:May 2, 2002 - v1
    Checksum:i42951BF97CA15DFA
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    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.

    Miscellaneous databases

    NextBioi 371321.
    PROi P58801.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P58801.
    Bgeei P58801.
    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

    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: October 1, 2014
    This is version 128 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