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Details on Person UniProt:O43353 RIPK2

Class:Id	ReferenceGeneProduct:63121
_chainChangeLog	chain:1-540 added on Sat February 7 2015
_displayName	UniProt:O43353 RIPK2
_timestamp	2025-08-15 22:11:24
chain	chain:1-540
checksum	575A692239505792
comment	FUNCTION Serine/threonine/tyrosine-protein kinase that plays an essential role in modulation of innate and adaptive immune responses (PubMed:14638696, PubMed:17054981, PubMed:21123652, PubMed:28656966, PubMed:9575181, PubMed:9642260). Acts as a key effector of NOD1 and NOD2 signaling pathways: upon activation by bacterial peptidoglycans, NOD1 and NOD2 oligomerize and recruit RIPK2 via CARD-CARD domains, leading to the formation of RIPK2 filaments (PubMed:17054981, PubMed:17562858, PubMed:21123652, PubMed:22607974, PubMed:28656966, PubMed:29452636, PubMed:30026309). Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3, as well as 'Met-1'-linked (linear) polyubiquitination by the LUBAC complex, becoming a scaffolding protein for downstream effectors (PubMed:22607974, PubMed:28545134, PubMed:29452636, PubMed:30026309, PubMed:30279485, PubMed:30478312). 'Met-1'-linked polyubiquitin chains attached to RIPK2 recruit IKBKG/NEMO, which undergoes 'Lys-63'-linked polyubiquitination in a RIPK2-dependent process (PubMed:17562858, PubMed:22607974, PubMed:29452636, PubMed:30026309). 'Lys-63'-linked polyubiquitin chains attached to RIPK2 serve as docking sites for TAB2 and TAB3 and mediate the recruitment of MAP3K7/TAK1 to IKBKG/NEMO, inducing subsequent activation of IKBKB/IKKB (PubMed:18079694). 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 (PubMed:18079694). The protein kinase activity is dispensable for the NOD1 and NOD2 signaling pathways (PubMed:29452636, PubMed:30026309). Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappa-B activation by NOD2 (PubMed:21887730). Also involved in adaptive immunity: plays a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation (PubMed:14638696). Plays a role in the inactivation of RHOA in response to NGFR signaling (PubMed:26646181).CATALYTIC ACTIVITY L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+)CATALYTIC ACTIVITY L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+)CATALYTIC ACTIVITY L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+)ACTIVITY REGULATION In the inactive state, the helix alphaC is packed against the helical, non-phosphorylated activation segment (AS) (PubMed:28545134). Upon activation, helix alphaC is displaced and the phosphorylated AS becomes disordered (PubMed:28545134). Specifically inhibited by GSK583, which blocks NOD2 signaling by interfering with XIAP binding to RIPK2 (PubMed:29452636). Specifically inhibited by CSLP37 and CSLP43, which blocks NOD2 signaling by interfering with XIAP binding to RIPK2 (PubMed:30026309).SUBUNIT Interacts (via CARD domain) with NOD2 (via CARD domain) (PubMed:15044951, PubMed:17355968, PubMed:19592251, PubMed:21887730, PubMed:27812135, PubMed:30279485, PubMed:30478312). Interacts (via CARD domain) with NOD1 (via CARD domain) (PubMed:17054981, PubMed:30478312). Homooligomer; following interaction with NOD1 or NOD2, homooligomerizes via its CARD domain and forms long filaments named RIPosomes (PubMed:30279485, PubMed:30478312). Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2 (PubMed:21887730). Interacts with ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK (PubMed:21887730). Interacts with MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling pathway (PubMed:18775659). Interacts with IKBKG/NEMO (PubMed:18079694). The polyubiquitinated protein interacts with MAP3K7/TAK1; interaction is indirect and is mediated by TAB2 and TAB3 that bind to polyubiquitin chains attached to RIPK2 (PubMed:18079694). Binds to CFLAR/CLARP and CASP1 via their CARD domains (PubMed:9575181). Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6 (PubMed:21931591). Interacts with NLRP10 (PubMed:22672233). Interacts with CARD9 (By similarity). Interacts with INAVA; the interaction takes place upon PRR stimulation (PubMed:28436939). Interacts (via CARD domain) with NGFR (via death domain) (PubMed:26646181). Interacts with IRGM; promoting RIPK2 degradation (PubMed:36221902).INTERACTION Recruited to the cell membrane by NOD2 following stimulation by bacterial peptidoglycans.ALTERNATIVE PRODUCTS Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node.DOMAIN Contains an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD) that mediates the recruitment of CARD-containing proteins.PTM Polyubiquitinated via both 'Lys-63'- and 'Met-1'-linked polyubiquitin following recruitment by NOD1 or NOD2, creating docking sites for downstream effectors, triggering activation of the NF-kappa-B and MAP kinases signaling (PubMed:22607974, PubMed:29452636, PubMed:30026309). 'Lys-63'-linked polyubiquitination by XIAP is essential for NOD2 signaling and promotes recruitment of the LUBAC complex (PubMed:22607974, PubMed:29452636, PubMed:30026309). Also polyubiquitinated with 'Lys-63'-linked chains by PELI3, BIRC2/c-IAP1 and BIRC3/c-IAP2 (PubMed:19464198, PubMed:21931591). Ubiquitinated on Lys-209 via 'Lys-63'-linked by ITCH (PubMed:18079694, PubMed:19592251). Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to attenuate NOD2-mediated inflammation and tissue damage (By similarity). Polyubiquitinated with 'Lys-63'-linked chains in response to Shigella infection, promoting its SQSTM1/p62-dependent autophagic degradation (PubMed:36221902). Undergoes 'Met-1'-linked polyubiquitination; the head-to-tail linear polyubiquitination is mediated by the LUBAC complex in response to NOD2 stimulation 'Met-1'-linked polyubiquitination (PubMed:23806334). 'Lys-63'-linked polyubiquitination by XIAP is required for recruimtent of the LUBAC complex and subsequent (PubMed:22607974). Linear polyubiquitination is restricted by FAM105B/otulin, probably to limit NOD2-dependent pro-inflammatory signaling activation of NF-kappa-B (PubMed:23806334). Ubiquitination at Lys-503 by ZNRF4 via 'Lys-48'-linked polyubiquitination promotes RIPK2 degradation by the proteasome; ubiquitination by ZNRF4 takes place during both acute and NOD2 tolerance conditions (PubMed:28656966).PTM Autophosphorylated (PubMed:16824733, PubMed:21123652, PubMed:28545134, PubMed:29452636). Phosphorylated at Ser-176, either via autophosphorylation or by LRRK2, enhancing activity (PubMed:16824733, PubMed:27830463). Autophosphorylation at Tyr-474 is required for effective NOD2 signaling (PubMed:21123652). Autophosphorylation is however not essential for NOD2 signaling (PubMed:29452636). Phosphorylation at Tyr-381 by Src kinase CSK occurs in a ARHGEF2-dependent manner and is required for NOD2-dependent innate immune activation (PubMed:21887730).PTM Degraded via selective autophagy following interaction with IRGM (PubMed:36221902). IRGM promotes NOD1/NOD2-RIPK2 RIPosome recruitment to autophagosome membranes (PubMed:36221902). RIPK2 biquitinated via 'Lys-63'-linked chains is then recognized by SQSTM1/p62, leading to the SQSTM1/p62-dependent autophagic degradation of the NOD1/NOD2-RIPK2 RIPosome (PubMed:36221902).PTM (Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178 by Yersinia YopJ prevents phosphorylation and activation, thereby promoting cell death.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.
description	recommendedName: Receptor-interacting serine/threonine-protein kinase 2 ecNumber evidence="8"2.7.11.1 alternativeName: fullName evidence="41"CARD-containing interleukin-1 beta-converting enzyme-associated kinase shortName evidence="41"CARD-containing IL-1 beta ICE-kinase alternativeName: fullName evidence="41"RIP-like-interacting CLARP kinase alternativeName: fullName evidence="42"Receptor-interacting protein 2 shortName evidence="42"RIP-2 alternativeName: Tyrosine-protein kinase RIPK2 ecNumber evidence="17"2.7.10.2
geneName	RIPK2 CARDIAK RICK RIP2 UNQ277/PRO314/PRO34092
identifier	O43353
isSequenceChanged	FALSE
keyword	3D-structure Acetylation Adaptive immunity Alternative splicing Apoptosis ATP-binding Cell membrane Cytoplasm Endoplasmic reticulum Immunity Innate immunity Isopeptide bond Kinase Membrane Nucleotide-binding Phosphoprotein Proteomics identification Reference proteome Serine/threonine-protein kinase Transferase Ubl conjugation
modified	[InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9841277] Weiser, Joel [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15
name	RIPK2
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:8962193] ENSEMBL:ENSG00000104312 RIPK2 [Homo sapiens]
secondaryIdentifier	RIPK2_HUMAN B7Z748 Q6UWF0
sequenceLength	540
species	[Species:48887] Homo sapiens
(isoformParent)	[ReferenceIsoform:245747] UniProt:O43353-2 RIPK2 [Homo sapiens] [ReferenceIsoform:401518] UniProt:O43353-1 RIPK2 [Homo sapiens]
(referenceEntity)	[EntityWithAccessionedSequence:168402] RIPK2 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:706483] Ub-209-RIPK2 [cytosol] [Homo sapiens]
(referenceSequence)	[ModifiedResidue:202457] phosphorylated residue at unknown position [GroupModifiedResidue:706472] ubiquitinylated lysine (K63polyUb [cytosol]) at 209
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No pathways have been reviewed or authored by UniProt:O43353 RIPK2 (63121)