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 27-MAR-2024, entry version 140. 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-protein kinase that plays an CC essential role in modulation of innate and adaptive immune responses. CC Acts as a key effector of NOD1 and NOD2 signaling pathways: upon CC activation by bacterial peptidoglycans, NOD1 and NOD2 oligomerize and CC recruit RIPK2 via CARD-CARD domains, leading to the formation of RIPK2 CC filaments. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys- CC 63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and CC BIRC3, as well as 'Met-1'-linked (linear) polyubiquitination by the CC LUBAC complex, becoming a scaffolding protein for downstream effectors. CC 'Met-1'-linked polyubiquitin chains attached to RIPK2 recruit CC IKBKG/NEMO, which undergoes 'Lys-63'-linked polyubiquitination in a CC RIPK2-dependent process. 'Lys-63'-linked polyubiquitin chains attached CC to RIPK2 serve as docking sites for TAB2 and TAB3 and mediate the CC recruitment of MAP3K7/TAK1 to IKBKG/NEMO, inducing subsequent CC activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF- CC kappa-B inhibitors and translocates into the nucleus where it activates CC the transcription of hundreds of genes involved in immune response, CC growth control, or protection against apoptosis. The protein kinase CC activity is dispensable for the NOD1 and NOD2 signaling pathways. CC Contributes to the tyrosine phosphorylation of the guanine exchange CC factor ARHGEF2 through Src tyrosine kinase leading to NF-kappa-B CC activation by NOD2. Also involved in adaptive immunity: plays a role CC during engagement of the T-cell receptor (TCR) in promoting BCL10 CC phosphorylation and subsequent NF-kappa-B activation. Plays a role in CC the inactivation of RHOA in response to NGFR signaling. CC {ECO:0000250|UniProtKB:O43353}. 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 Evidence={ECO:0000250|UniProtKB:O43353}; 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; Evidence={ECO:0000250|UniProtKB:O43353}; 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 -!- ACTIVITY REGULATION: In the inactive state, the helix alphaC is packed CC against the helical, non-phosphorylated activation segment (AS). Upon CC activation, helix alphaC is displaced and the phosphorylated AS becomes CC disordered. {ECO:0000250|UniProtKB:O43353}. CC -!- SUBUNIT: Interacts (via CARD domain) with NOD2 (via CARD domain) (By CC similarity). Interacts (via CARD domain) with NOD1 (via CARD domain) CC (By similarity). Homooligomer; following interaction with NOD1 or NOD2, CC homooligomerizes via its CARD domain and forms long filaments named CC RIPosomes (By similarity). Found in a signaling complex consisting of CC at least ARHGEF2, NOD2 and RIPK2 (By similarity). Interacts with CC ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by CC Src kinase CSK (By similarity). Interacts with MAP3K4; this interaction CC sequesters RIPK2 from the NOD2 signaling pathway (By similarity). CC Interacts with IKBKG/NEMO (By similarity). The polyubiquitinated CC protein interacts with MAP3K7/TAK1; interaction is indirect and is CC mediated by TAB2 and TAB3 that bind to polyubiquitin chains attached to CC RIPK2 (By similarity). Binds to CFLAR/CLARP and CASP1 via their CARD CC domains (By similarity). Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, CC TRAF2, TRAF5 and TRAF6 (By similarity). Interacts with NLRP10 (By CC similarity). Interacts with CARD9 (By similarity). Interacts with CC INAVA; the interaction takes place upon PRR stimulation (By CC similarity). Interacts (via CARD domain) with NGFR (via death domain) CC (By similarity). Interacts with IRGM; promoting RIPK2 degradation (By CC similarity). {ECO:0000250|UniProtKB:O43353, CC ECO:0000250|UniProtKB:P58801}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O43353}. Cell CC membrane {ECO:0000250|UniProtKB:O43353}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:O43353}. Endoplasmic reticulum CC {ECO:0000250|UniProtKB:O43353}. Note=Recruited to the cell membrane by CC NOD2 following stimulation by bacterial peptidoglycans. CC {ECO:0000250|UniProtKB:O43353}. 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: Polyubiquitinated via both 'Lys-63'- and 'Met-1'-linked CC polyubiquitin following recruitment by NOD1 or NOD2, creating docking CC sites for downstream effectors, triggering activation of the NF-kappa-B CC and MAP kinases signaling. 'Lys-63'-linked polyubiquitination by XIAP CC is essential for NOD2 signaling and promotes recruitment of the LUBAC CC complex. Also polyubiquitinated with 'Lys-63'-linked chains by PELI3, CC BIRC2/c-IAP1 and BIRC3/c-IAP2. Ubiquitinated on Lys-209 via 'Lys-63'- CC linked by ITCH (By similarity). Undergoes 'Lys-63'-linked CC deubiquitination by MYSM1 to attenuate NOD2-mediated inflammation and CC tissue damage (By similarity). Polyubiquitinated with 'Lys-63'-linked CC chains in response to Shigella infection, promoting its SQSTM1/p62- CC dependent autophagic degradation. Undergoes 'Met-1'-linked CC polyubiquitination; the head-to-tail linear polyubiquitination is CC mediated by the LUBAC complex in response to NOD2 stimulation 'Met-1'- CC linked polyubiquitination. 'Lys-63'-linked polyubiquitination by XIAP CC is required for recruimtent of the LUBAC complex and subsequent. Linear CC polyubiquitination is restricted by FAM105B/otulin, probably to limit CC NOD2-dependent pro-inflammatory signaling activation of NF-kappa-B (By CC similarity). {ECO:0000250|UniProtKB:O43353, CC ECO:0000250|UniProtKB:P58801}. CC -!- PTM: Autophosphorylated (By similarity). Phosphorylated at Ser-176, CC either via autophosphorylation or by LRRK2, enhancing activity (By CC similarity). Autophosphorylation at Tyr-472 is required for effective CC NOD2 signaling. Autophosphorylation is however not essential for NOD2 CC signaling (By similarity). {ECO:0000250|UniProtKB:O43353}. CC -!- PTM: Degraded via selective autophagy following interaction with IRGM. CC IRGM promotes NOD1/NOD2-RIPK2 RIPosome recruitment to autophagosome CC membranes. RIPK2 biquitinated via 'Lys-63'-linked chains is then CC recognized by SQSTM1/p62, leading to the SQSTM1/p62-dependent CC autophagic degradation of the NOD1/NOD2-RIPK2 RIPosome. CC {ECO:0000250|UniProtKB:O43353}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; BC102829; AAI02830.1; -; mRNA. DR RefSeq; NP_001029782.1; NM_001034610.2. DR AlphaFoldDB; Q3SZJ2; -. DR SMR; Q3SZJ2; -. DR STRING; 9913.ENSBTAP00000020312; -. DR PaxDb; 9913-ENSBTAP00000054150; -. DR Ensembl; ENSBTAT00000020312.3; ENSBTAP00000020312.2; ENSBTAG00000015271.4. 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; IPQCNIL; -. DR OrthoDB; 5349889at2759; -. DR Reactome; R-BTA-168638; NOD1/2 Signaling Pathway. DR Reactome; R-BTA-202424; Downstream TCR signaling. DR Reactome; R-BTA-209543; p75NTR recruits signalling complexes. DR Reactome; R-BTA-450302; activated TAK1 mediates p38 MAPK activation. DR Reactome; R-BTA-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1. DR Reactome; R-BTA-5689896; Ovarian tumor domain proteases. DR Proteomes; UP000009136; Chromosome 14. DR Bgee; ENSBTAG00000015271; Expressed in spermatid and 103 other cell types or 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:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. 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; ISS:UniProtKB. DR GO; GO:0035591; F:signaling adaptor activity; ISS:UniProtKB. DR GO; GO:0005102; F:signaling receptor binding; 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:0007249; P:canonical NF-kappaB signal transduction; ISS:UniProtKB. 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: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:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IBA:GO_Central. 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:0033092; P:positive regulation of immature T cell proliferation in thymus; 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:1902523; P:positive regulation of protein K63-linked ubiquitination; ISS:UniProtKB. 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:0032729; P:positive regulation of type II interferon production; IEA:Ensembl. DR GO; GO:1904417; P:positive regulation of xenophagy; IEA:Ensembl. DR GO; GO:0051260; P:protein homooligomerization; 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; Death Domain, Fas; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 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 PANTHER; PTHR23257:SF985; RECEPTOR-INTERACTING SERINE_THREONINE-PROTEIN KINASE 3; 1. DR PANTHER; PTHR23257; SERINE-THREONINE PROTEIN KINASE; 1. 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; DEATH domain; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 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; Cell membrane; Cytoplasm; KW Endoplasmic reticulum; Immunity; Innate immunity; Isopeptide bond; Kinase; KW Membrane; Nucleotide-binding; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; 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 65..73 FT /note="Helix alphaC" FT /evidence="ECO:0000250|UniProtKB:O43353" FT REGION 167..193 FT /note="Activation segment (AS)" FT /evidence="ECO:0000250|UniProtKB:O43353" 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 174 FT /note="Phosphoserine; alternate" FT /evidence="ECO:0000250|UniProtKB:O43353" FT MOD_RES 176 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:O43353" FT MOD_RES 178 FT /note="Phosphoserine; alternate" FT /evidence="ECO:0000250|UniProtKB:O43353" FT MOD_RES 180 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O43353" FT MOD_RES 181 FT /note="Phosphoserine; alternate" 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" FT CROSSLNK 536 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 //