RIPK2_BOVIN
ID RIPK2_BOVIN Reviewed; 540 AA.
AC Q3SZJ2;
DT 11-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 1.
DT 03-AUG-2022, entry version 131.
DE RecName: Full=Receptor-interacting serine/threonine-protein kinase 2;
DE EC=2.7.11.1;
DE AltName: Full=Tyrosine-protein kinase RIPK2;
DE EC=2.7.10.2;
GN Name=RIPK2;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Crossbred X Angus; TISSUE=Ileum;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Serine/threonine/tyrosine kinase that plays an essential role
CC in modulation of innate and adaptive immune responses. Upon stimulation
CC by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize
CC and recruit RIPK2 through CARD-CARD domains. Once recruited,
CC autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by
CC E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated
CC protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and
CC induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent
CC activation of IKBKB/IKKB. In turn, NF-kappa-B is release from NF-kappa-
CC B inhibitors and translocates into the nucleus where it activates the
CC transcription of hundreds of genes involved in immune response, growth
CC control, or protection against apoptosis. Also plays a role during
CC engagement of the T-cell receptor (TCR) in promoting BCL10
CC phosphorylation and subsequent NF-kappa-B activation (By similarity).
CC Plays a role in the inactivation of RHOA in response to NGFR signaling
CC (By similarity). {ECO:0000250|UniProtKB:O43353,
CC ECO:0000250|UniProtKB:P58801}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10027};
CC -!- SUBUNIT: Found in a signaling complex consisting of at least ARHGEF2,
CC NOD2 and RIPK2. Interacts with ARHGEF2; the interaction mediates
CC tyrosine phosphorylation of RIPK2 by Src kinase CSK. Binds to
CC CFLAR/CLARP and CASP1 via their CARD domains. Binds to BIRC3/c-IAP1 and
CC BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6. May be a component of both
CC the TNFRSF1A and TNRFSF5/CD40 receptor complex. Interacts with NOD1.
CC Interacts (via CARD domain) with NOD2 (via CARD domain). Interacts with
CC MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling
CC pathway. Interacts with IKBKG/NEMO. The polyubiquitinated protein
CC interacts with MAP3K7/TAK1. Interacts with XIAP/BIRC4. Interacts with
CC NLRP10. Interacts with CARD9. Interacts with INAVA; the interaction
CC takes place upon PRR stimulation. Interacts (via CARD domain) with NGFR
CC (via death domain). {ECO:0000250|UniProtKB:O43353}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305}.
CC -!- DOMAIN: Contains an N-terminal kinase domain and a C-terminal caspase
CC activation and recruitment domain (CARD) that mediates the recruitment
CC of CARD-containing proteins. {ECO:0000250|UniProtKB:P51617}.
CC -!- PTM: Autophosphorylated. Autophosphorylation at Tyr-472 is necessary
CC for effective NOD2 signaling. {ECO:0000250|UniProtKB:P51617}.
CC -!- PTM: Ubiquitinated on Lys-209; undergoes 'Lys-63'-linked
CC polyubiquitination catalyzed by ITCH. Polyubiquitinated with 'Lys-48'
CC and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to
CC activation of NF-kappa-B. Also undergoes 'Met-1'-linked
CC polyubiquitination; the head-to-tail linear polyubiquitination is
CC mediated by the LUBAC complex in response to NOD2 stimulation. Linear
CC polyubiquitination is restricted by FAM105B/otulin, probably to limit
CC NOD2-dependent pro-inflammatory signaling activation of NF-kappa-B.
CC Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to attenuate NOD2-
CC mediated inflammation and tissue damage (By similarity).
CC {ECO:0000250|UniProtKB:P51617, ECO:0000250|UniProtKB:P58801}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. {ECO:0000305}.
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DR EMBL; BC102829; AAI02830.1; -; mRNA.
DR RefSeq; NP_001029782.1; NM_001034610.2.
DR AlphaFoldDB; Q3SZJ2; -.
DR SMR; Q3SZJ2; -.
DR STRING; 9913.ENSBTAP00000054150; -.
DR PRIDE; Q3SZJ2; -.
DR Ensembl; ENSBTAT00000020312; ENSBTAP00000020312; ENSBTAG00000015271.
DR GeneID; 534407; -.
DR KEGG; bta:534407; -.
DR CTD; 8767; -.
DR VEuPathDB; HostDB:ENSBTAG00000015271; -.
DR VGNC; VGNC:33982; RIPK2.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00940000156113; -.
DR HOGENOM; CLU_000288_7_35_1; -.
DR InParanoid; Q3SZJ2; -.
DR OMA; CPVNHSW; -.
DR OrthoDB; 436531at2759; -.
DR Reactome; R-BTA-202424; Downstream TCR signaling.
DR Proteomes; UP000009136; Chromosome 14.
DR Bgee; ENSBTAG00000015271; Expressed in spermatid and 103 other tissues.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0032991; C:protein-containing complex; ISS:UniProtKB.
DR GO; GO:0031982; C:vesicle; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0050700; F:CARD domain binding; IEA:Ensembl.
DR GO; GO:0089720; F:caspase binding; IEA:Ensembl.
DR GO; GO:0004706; F:JUN kinase kinase kinase activity; IBA:GO_Central.
DR GO; GO:0030274; F:LIM domain binding; IEA:Ensembl.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0042803; F:protein homodimerization activity; IEA:Ensembl.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0005102; F:signaling receptor binding; IEA:Ensembl.
DR GO; GO:0097202; P:activation of cysteine-type endopeptidase activity; IEA:Ensembl.
DR GO; GO:0002250; P:adaptive immune response; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0035739; P:CD4-positive, alpha-beta T cell proliferation; IEA:Ensembl.
DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Ensembl.
DR GO; GO:0071225; P:cellular response to muramyl dipeptide; ISS:UniProtKB.
DR GO; GO:0071224; P:cellular response to peptidoglycan; IEA:Ensembl.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0033080; P:immature T cell proliferation in thymus; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0070427; P:nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Ensembl.
DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:2000563; P:positive regulation of CD4-positive, alpha-beta T cell proliferation; IEA:Ensembl.
DR GO; GO:0032722; P:positive regulation of chemokine production; IEA:Ensembl.
DR GO; GO:0001961; P:positive regulation of cytokine-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IBA:GO_Central.
DR GO; GO:0033092; P:positive regulation of immature T cell proliferation in thymus; IEA:Ensembl.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IEA:Ensembl.
DR GO; GO:0032743; P:positive regulation of interleukin-2 production; IEA:Ensembl.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:UniProtKB.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl.
DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Ensembl.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; ISS:UniProtKB.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; ISS:UniProtKB.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISS:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; IEA:Ensembl.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IEA:Ensembl.
DR GO; GO:0045627; P:positive regulation of T-helper 1 cell differentiation; IEA:Ensembl.
DR GO; GO:0002827; P:positive regulation of T-helper 1 type immune response; IEA:Ensembl.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:UniProtKB.
DR GO; GO:1904417; P:positive regulation of xenophagy; IEA:Ensembl.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0070555; P:response to interleukin-1; IEA:Ensembl.
DR GO; GO:0070671; P:response to interleukin-12; IEA:Ensembl.
DR GO; GO:0070673; P:response to interleukin-18; IEA:Ensembl.
DR GO; GO:0050852; P:T cell receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; IEA:Ensembl.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IEA:Ensembl.
DR GO; GO:0098792; P:xenophagy; IEA:Ensembl.
DR CDD; cd08786; CARD_RIP2_CARD3; 1.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR042149; CARD_RIP2.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017322; Rcpt-int_Ser/Thr_kinase-2.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00619; CARD; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PIRSF; PIRSF037921; STPK_RIP2; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50209; CARD; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 2: Evidence at transcript level;
KW Adaptive immunity; Apoptosis; ATP-binding; Cytoplasm; Immunity;
KW Innate immunity; Isopeptide bond; Kinase; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Ubl conjugation.
FT CHAIN 1..540
FT /note="Receptor-interacting serine/threonine-protein kinase
FT 2"
FT /id="PRO_0000245586"
FT DOMAIN 18..294
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 432..524
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 318..367
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 338..367
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 146
FT /note="Proton acceptor"
FT BINDING 24..32
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 47
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 168
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43353"
FT MOD_RES 176
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:O43353"
FT MOD_RES 363
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43353"
FT MOD_RES 391
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43353"
FT MOD_RES 472
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:O43353"
FT MOD_RES 525
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43353"
FT MOD_RES 527
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43353"
FT MOD_RES 529
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43353"
FT MOD_RES 537
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43353"
FT CROSSLNK 209
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:O43353"
SQ SEQUENCE 540 AA; 61106 MW; 2F54BD72A747970F CRC64;
MSAEPVCSAL PAIPYHKLAD LRYLSRGASG TVSSARHADW RVQVAVKHLH IHSPLLDSER
NDVLREAEIL HKARFSYILP ILGICNEPEF LGIVTEYMPN GSLNELLHRK IEYPDVPWPL
RFRILHEIAL GVNYLHNMNP PLLHHDLKTQ NILLDNEFHV KIADFGLSKW RMMSLSQSRS
SKSAPEGGTI VYMPPENYEP GQKARASVKH DIYSYAIIIW EVLSRKQPFE DVTNPLQIMY
SVSQGHRPDT NEESLPFDIP HRALMISLIE SGWAQNPDER PSFLKCLIEL EPVLRTFEEI
TFLEAVIQLK KTKLQNASRT VHLSDKKKRE LSPNIPVNSG PREESCGSSQ LHKTSGSPGT
SRSLSAPQDK DFLSAKTQDF SALHQCSVNH SRNSDFCVDC QVAFCDHRTA PCSLAIVNPL
SAEGNSGRFQ PGIAQQWIQS KREDIVSQMT EACLNQSLDA LLSRDLIMKE DYELISTKPT
RTSKVRQLLD TTDIQGEEFA RVIVQKLKDN KQMGLQPYPE ILVLSQSPSL NFFHNKSHKK
