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O43353

- RIPK2_HUMAN

UniProt

O43353 - RIPK2_HUMAN

Protein

Receptor-interacting serine/threonine-protein kinase 2

Gene

RIPK2

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 159 (01 Oct 2014)
      Sequence version 2 (01 Nov 1998)
      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. 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)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei47 – 471ATP
    Active sitei146 – 1461Proton acceptor

    Regions

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

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. CARD domain binding Source: UniProtKB
    3. LIM domain binding Source: UniProtKB
    4. non-membrane spanning protein tyrosine kinase activity Source: UniProtKB-EC
    5. protein binding Source: UniProtKB
    6. protein homodimerization activity Source: BHF-UCL
    7. protein serine/threonine kinase activity Source: ProtInc
    8. signal transducer activity Source: ProtInc

    GO - Biological processi

    1. activation of MAPK activity Source: Reactome
    2. adaptive immune response Source: UniProtKB
    3. apoptotic process Source: ProtInc
    4. cellular response to lipoteichoic acid Source: Ensembl
    5. cellular response to muramyl dipeptide Source: UniProtKB
    6. cellular response to peptidoglycan Source: Ensembl
    7. defense response to Gram-positive bacterium Source: Ensembl
    8. I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
    9. inflammatory response Source: ProtInc
    10. innate immune response Source: UniProtKB
    11. JNK cascade Source: Reactome
    12. lipopolysaccharide-mediated signaling pathway Source: Ensembl
    13. MyD88-dependent toll-like receptor signaling pathway Source: Reactome
    14. MyD88-independent toll-like receptor signaling pathway Source: Reactome
    15. negative regulation of apoptotic process Source: Reactome
    16. neurotrophin TRK receptor signaling pathway Source: Reactome
    17. nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway Source: Reactome
    18. nucleotide-binding oligomerization domain containing 1 signaling pathway Source: Ensembl
    19. nucleotide-binding oligomerization domain containing 2 signaling pathway Source: UniProtKB
    20. nucleotide-binding oligomerization domain containing signaling pathway Source: Reactome
    21. positive regulation of alpha-beta T cell proliferation Source: Ensembl
    22. positive regulation of apoptotic process Source: Ensembl
    23. positive regulation of chemokine production Source: Ensembl
    24. positive regulation of cytokine-mediated signaling pathway Source: Ensembl
    25. positive regulation of ERK1 and ERK2 cascade Source: Ensembl
    26. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
    27. positive regulation of immature T cell proliferation Source: Ensembl
    28. positive regulation of interferon-alpha production Source: BHF-UCL
    29. positive regulation of interferon-beta production Source: BHF-UCL
    30. positive regulation of interferon-gamma production Source: Ensembl
    31. positive regulation of interleukin-12 production Source: BHF-UCL
    32. positive regulation of interleukin-2 production Source: Ensembl
    33. positive regulation of interleukin-6 production Source: Ensembl
    34. positive regulation of JNK cascade Source: Ensembl
    35. positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
    36. positive regulation of peptidyl-serine phosphorylation Source: UniProtKB
    37. positive regulation of peptidyl-threonine phosphorylation Source: UniProtKB
    38. positive regulation of peptidyl-tyrosine phosphorylation Source: UniProtKB
    39. positive regulation of protein ubiquitination Source: UniProtKB
    40. positive regulation of T-helper 1 cell differentiation Source: Ensembl
    41. positive regulation of T-helper 1 type immune response Source: Ensembl
    42. positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
    43. positive regulation of tumor necrosis factor production Source: Ensembl
    44. response to exogenous dsRNA Source: Ensembl
    45. response to interleukin-1 Source: Ensembl
    46. response to interleukin-12 Source: Ensembl
    47. response to interleukin-18 Source: Ensembl
    48. signal transduction Source: ProtInc
    49. stress-activated MAPK cascade Source: Reactome
    50. T cell proliferation Source: Ensembl
    51. T cell receptor signaling pathway Source: UniProtKB
    52. toll-like receptor 10 signaling pathway Source: Reactome
    53. toll-like receptor 2 signaling pathway Source: MGI
    54. toll-like receptor 3 signaling pathway Source: Reactome
    55. toll-like receptor 4 signaling pathway Source: Reactome
    56. toll-like receptor 5 signaling pathway Source: Reactome
    57. toll-like receptor 9 signaling pathway Source: Reactome
    58. toll-like receptor signaling pathway Source: Reactome
    59. toll-like receptor TLR1:TLR2 signaling pathway Source: Reactome
    60. toll-like receptor TLR6:TLR2 signaling pathway Source: Reactome
    61. TRIF-dependent toll-like receptor signaling pathway Source: Reactome

    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

    BRENDAi2.7.10.2. 2681.
    ReactomeiREACT_12555. Downstream TCR signaling.
    REACT_13415. p75NTR recruits signalling complexes.
    REACT_21281. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_21368. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
    REACT_21399. activated TAK1 mediates p38 MAPK activation.
    REACT_22442. Interleukin-1 signaling.
    REACT_75776. NOD1/2 Signaling Pathway.
    SignaLinkiO43353.

    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
    ProteomesiUP000005640: Chromosome 8

    Organism-specific databases

    HGNCiHGNC:10020. 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

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi47 – 471K → A: Abolishes kinase activity. 2 Publications
    Mutagenesisi47 – 471K → M: Reduces FAS-mediated apoptosis. 2 Publications
    Mutagenesisi146 – 1461D → N: Abolishes kinase activity. 1 Publication
    Mutagenesisi209 – 2091K → R: Complete loss of polyubiquitination. 1 Publication
    Mutagenesisi381 – 3811Y → A: Prevents phosphorylation. Reduces serine and threonine phosphorylation of ARHGEF2.
    Mutagenesisi444 – 4441R → E: Abolishes interaction with NOD1. 1 Publication
    Mutagenesisi474 – 4741Y → F: Decreases interaction with NOD2. 1 Publication
    Mutagenesisi483 – 4831R → E: Abolishes interaction with NOD1. 1 Publication
    Mutagenesisi488 – 4881R → E: Abolishes interaction with NOD1. 1 Publication

    Organism-specific databases

    PharmGKBiPA34395.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 540540Receptor-interacting serine/threonine-protein kinase 2PRO_0000086608Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei168 – 1681Phosphoserine1 Publication
    Modified residuei176 – 1761Phosphoserine; by autocatalysis1 Publication
    Cross-linki209 – 209Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
    Modified residuei363 – 3631Phosphoserine2 Publications
    Modified residuei381 – 3811Phosphotyrosine; by CSK1 Publication
    Modified residuei393 – 3931Phosphoserine1 Publication
    Modified residuei474 – 4741Phosphotyrosine; by autocatalysis1 Publication
    Modified residuei527 – 5271Phosphoserine2 Publications
    Modified residuei529 – 5291Phosphoserine1 Publication
    Modified residuei531 – 5311Phosphoserine1 Publication
    Modified residuei539 – 5391Phosphoserine2 Publications

    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.7 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

    MaxQBiO43353.
    PaxDbiO43353.
    PRIDEiO43353.

    PTM databases

    PhosphoSiteiO43353.

    Expressioni

    Tissue specificityi

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

    Gene expression databases

    ArrayExpressiO43353.
    BgeeiO43353.
    CleanExiHS_RIPK2.
    GenevestigatoriO43353.

    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). 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 CARD9.7 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    BIRC2Q134903EBI-358522,EBI-514538
    BIRC3Q134893EBI-358522,EBI-517709
    MAVSQ7Z4343EBI-358522,EBI-995373
    TRAF3Q131145EBI-358522,EBI-357631

    Protein-protein interaction databases

    BioGridi114300. 39 interactions.
    DIPiDIP-27518N.
    IntActiO43353. 11 interactions.
    MINTiMINT-90752.
    STRINGi9606.ENSP00000220751.

    Structurei

    Secondary structure

    1
    540
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi15 – 173
    Beta strandi18 – 269
    Beta strandi28 – 3710
    Turni38 – 403
    Beta strandi43 – 497
    Helixi56 – 7217
    Beta strandi81 – 877
    Beta strandi90 – 967
    Helixi103 – 1086
    Turni110 – 1123
    Helixi118 – 13619
    Beta strandi138 – 1403
    Helixi149 – 1513
    Beta strandi152 – 1543
    Beta strandi160 – 1623
    Helixi190 – 1923
    Helixi195 – 1973
    Helixi210 – 22415
    Turni228 – 2314
    Helixi235 – 2439
    Turni252 – 2543
    Helixi262 – 27211
    Helixi277 – 2793
    Helixi283 – 29513
    Helixi300 – 31314

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    4C8BX-ray2.75A/B8-317[»]
    ProteinModelPortaliO43353.
    SMRiO43353. Positions 9-316.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini18 – 294277Protein kinasePROSITE-ProRule annotationAdd
    BLAST
    Domaini432 – 52493CARDPROSITE-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.

    Sequence similaritiesi

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

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000136856.
    HOVERGENiHBG054242.
    InParanoidiO43353.
    KOiK08846.
    OMAiYPDVAWP.
    OrthoDBiEOG78H3SS.
    PhylomeDBiO43353.
    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]

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. Align

    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

    MNGEAICSAL PTIPYHKLAD LRYLSRGASG TVSSARHADW RVQVAVKHLH    50
    IHTPLLDSER KDVLREAEIL HKARFSYILP ILGICNEPEF LGIVTEYMPN 100
    GSLNELLHRK TEYPDVAWPL RFRILHEIAL GVNYLHNMTP PLLHHDLKTQ 150
    NILLDNEFHV KIADFGLSKW RMMSLSQSRS SKSAPEGGTI IYMPPENYEP 200
    GQKSRASIKH DIYSYAVITW EVLSRKQPFE DVTNPLQIMY SVSQGHRPVI 250
    NEESLPYDIP HRARMISLIE SGWAQNPDER PSFLKCLIEL EPVLRTFEEI 300
    TFLEAVIQLK KTKLQSVSSA IHLCDKKKME LSLNIPVNHG PQEESCGSSQ 350
    LHENSGSPET SRSLPAPQDN DFLSRKAQDC YFMKLHHCPG NHSWDSTISG 400
    SQRAAFCDHK TTPCSSAIIN PLSTAGNSER LQPGIAQQWI QSKREDIVNQ 450
    MTEACLNQSL DALLSRDLIM KEDYELVSTK PTRTSKVRQL LDTTDIQGEE 500
    FAKVIVQKLK DNKQMGLQPY PEILVVSRSP SLNLLQNKSM 540
    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

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti271 – 2711S → G in BAH13484. (PubMed:14702039)Curated
    Sequence conflicti514 – 5141Q → R in BAH13484. (PubMed:14702039)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti259 – 2591I → T.1 Publication
    Corresponds to variant rs2230801 [ dbSNP | Ensembl ].
    VAR_041045
    Natural varianti268 – 2681L → V.1 Publication
    Corresponds to variant rs35004667 [ dbSNP | Ensembl ].
    VAR_041046
    Natural varianti313 – 3131K → N.1 Publication
    Corresponds to variant rs35395048 [ dbSNP | Ensembl ].
    VAR_041047

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 137137Missing in isoform 2. 2 PublicationsVSP_013266Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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_005251092.2. [O43353-2]
    UniGeneiHs.103755.

    Genome annotation databases

    EnsembliENST00000220751; ENSP00000220751; ENSG00000104312. [O43353-1]
    GeneIDi8767.
    KEGGihsa:8767.
    UCSCiuc003yee.3. human. [O43353-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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 .
    CCDSi CCDS6247.1. [O43353-1 ]
    RefSeqi NP_003812.1. NM_003821.5. [O43353-1 ]
    XP_005251149.1. XM_005251092.2. [O43353-2 ]
    UniGenei Hs.103755.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    4C8B X-ray 2.75 A/B 8-317 [» ]
    ProteinModelPortali O43353.
    SMRi O43353. Positions 9-316.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 114300. 39 interactions.
    DIPi DIP-27518N.
    IntActi O43353. 11 interactions.
    MINTi MINT-90752.
    STRINGi 9606.ENSP00000220751.

    Chemistry

    BindingDBi O43353.
    ChEMBLi CHEMBL5014.
    GuidetoPHARMACOLOGYi 2190.

    PTM databases

    PhosphoSitei O43353.

    Proteomic databases

    MaxQBi O43353.
    PaxDbi O43353.
    PRIDEi O43353.

    Protocols and materials databases

    DNASUi 8767.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000220751 ; ENSP00000220751 ; ENSG00000104312 . [O43353-1 ]
    GeneIDi 8767.
    KEGGi hsa:8767.
    UCSCi uc003yee.3. human. [O43353-1 ]

    Organism-specific databases

    CTDi 8767.
    GeneCardsi GC08P090769.
    HGNCi HGNC:10020. RIPK2.
    HPAi HPA015273.
    HPA016499.
    MIMi 603455. gene.
    neXtProti NX_O43353.
    PharmGKBi PA34395.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000136856.
    HOVERGENi HBG054242.
    InParanoidi O43353.
    KOi K08846.
    OMAi YPDVAWP.
    OrthoDBi EOG78H3SS.
    PhylomeDBi O43353.
    TreeFami TF106506.

    Enzyme and pathway databases

    BRENDAi 2.7.10.2. 2681.
    Reactomei REACT_12555. Downstream TCR signaling.
    REACT_13415. p75NTR recruits signalling complexes.
    REACT_21281. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_21368. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
    REACT_21399. activated TAK1 mediates p38 MAPK activation.
    REACT_22442. Interleukin-1 signaling.
    REACT_75776. NOD1/2 Signaling Pathway.
    SignaLinki O43353.

    Miscellaneous databases

    GeneWikii RIPK2.
    GenomeRNAii 8767.
    NextBioi 32880.
    PROi O43353.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O43353.
    Bgeei O43353.
    CleanExi HS_RIPK2.
    Genevestigatori O43353.

    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. "RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis."
      Inohara N., del Peso L., Koseki T., Chen S., Nunez G.
      J. Biol. Chem. 273:12296-12300(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS OF LYS-47.
    2. "RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase."
      McCarthy J.V., Ni J., Dixit V.M.
      J. Biol. Chem. 273:16968-16975(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS OF LYS-47.
      Tissue: Endothelial cell.
    3. "Identification of CARDIAK, a RIP-like kinase that associates with caspase-1."
      Thome M., Hofmann K., Burns K., Martinon F., Bodmer J.-L., Mattmann C., Tschopp J.
      Curr. Biol. 8:885-888(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS OF ASP-146.
      Tissue: Pancreatic adenocarcinoma.
    4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
    5. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
      Tissue: Synovium.
    6. "DNA sequence and analysis of human chromosome 8."
      Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., Asakawa T.
      , Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N., Lander E.S.
      Nature 439:331-335(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    7. "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] (ISOFORM 1).
      Tissue: Skin.
    8. "Rip2 participates in Bcl10 signaling and T-cell receptor-mediated NF-kappaB activation."
      Ruefli-Brasse A.A., Lee W.P., Hurst S., Dixit V.M.
      J. Biol. Chem. 279:1570-1574(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    9. "Identification of a regulatory autophosphorylation site in the serine-threonine kinase RIP2."
      Dorsch M., Wang A., Cheng H., Lu C., Bielecki A., Charron K., Clauser K., Ren H., Polakiewicz R.D., Parsons T., Li P., Ocain T., Xu Y.
      Cell. Signal. 18:2223-2229(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-176.
    10. "Solution structure of NOD1 CARD and mutational analysis of its interaction with the CARD of downstream kinase RICK."
      Manon F., Favier A., Nunez G., Simorre J.P., Cusack S.
      J. Mol. Biol. 365:160-174(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH NOD1, MUTAGENESIS OF ARG-444; ARG-483 AND ARG-488.
    11. "MEKK4 sequesters RIP2 to dictate NOD2 signal specificity."
      Clark N.M., Marinis J.M., Cobb B.A., Abbott D.W.
      Curr. Biol. 18:1402-1408(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MAP3K4.
    12. "A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation."
      Hasegawa M., Fujimoto Y., Lucas P.C., Nakano H., Fukase K., Nunez G., Inohara N.
      EMBO J. 27:373-383(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH IKBKG/NEMO AND MAP3K7/TAK1, FUNCTION, UBIQUITINATION AT LYS-209, MUTAGENESIS OF LYS-209.
    13. "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
      Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
      Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-363; SER-527 AND SER-539, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    14. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-531, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    15. "ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways."
      Tao M., Scacheri P.C., Marinis J.M., Harhaj E.W., Matesic L.E., Abbott D.W.
      Curr. Biol. 19:1255-1263(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION BY ITCH, INTERACTION WITH NOD2.
    16. "Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2."
      Bertrand M.J., Doiron K., Labbe K., Korneluk R.G., Barker P.A., Saleh M.
      Immunity 30:789-801(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION BY BIRC2 AND BIRC3.
    17. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-168; SER-363; SER-393; SER-527 AND SER-539, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    18. "Inhibition of RIP2's tyrosine kinase activity limits NOD2-driven cytokine responses."
      Tigno-Aranjuez J.T., Asara J.M., Abbott D.W.
      Genes Dev. 24:2666-2677(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, PHOSPHORYLATION AT TYR-474, MUTAGENESIS OF TYR-474.
    19. "Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
      Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
      Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-529, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    20. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    21. "cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4)."
      Bertrand M.J., Lippens S., Staes A., Gilbert B., Roelandt R., De Medts J., Gevaert K., Declercq W., Vandenabeele P.
      PLoS ONE 6:E22356-E22356(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION BY BIRC2/C-IAP1 AND BIRC3/C-IAP2, INTERACTION WITH BIRC2/C-IAP1; BIRC3/C-IAP2 AND XIAP/BIRC4.
    22. Cited for: INTERACTION WITH NLRP10.
    23. Cited for: FUNCTION, IDENTIFICATION IN A COMPLEX WITH ARHGEF2 AND NOD2, INTERACTION WITH ARHGEF2 AND NOD2, PHOSPHORYLATION AT TYR-381.
    24. Cited for: UBIQUITINATION, DEUBIQUITINATION.
    25. "Patterns of somatic mutation in human cancer genomes."
      Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.
      , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
      Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS [LARGE SCALE ANALYSIS] THR-259; VAL-268 AND ASN-313.

    Entry informationi

    Entry nameiRIPK2_HUMAN
    AccessioniPrimary (citable) accession number: O43353
    Secondary accession number(s): B7Z748, Q6UWF0
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: May 2, 2002
    Last sequence update: November 1, 1998
    Last modified: October 1, 2014
    This is version 159 of the entry and version 2 of the sequence. [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. Human chromosome 8
      Human chromosome 8: entries, gene names and cross-references to MIM
    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 and mouse protein kinases
      Human and mouse protein kinases: classification and index
    7. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3