RIPK2
entrez
8767
canonical
uniprot
O43353
canonical
ensembl
ENSG00000104312
resolver
ensp
ENSP00000220751
resolver
genesymbol
RIPK2
resolver
genesymbol_syn
CARDIAK
resolver
genesymbol_syn
RICK
resolver
genesymbol_syn
RIP2
resolver
hgnc
HGNC:10020
resolver
uniprot
A0A0S2Z4Z8
resolver
uniprot
B7Z748
resolver
uniprot
Q6UWF0
resolver
uniprot_entry
A0A0S2Z4Z8_HUMAN
resolver
uniprot_entry
RIPK2_HUMAN
resolver
uniprot_sec
B7Z748
resolver
uniprot_sec
Q6UWF0
resolver
activity_regulation
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). {ECO:0000269|PubMed:28545134, ECO:0000269|PubMed:29452636, ECO:0000269|PubMed:30026309}.
uniprot
proteins
amino_acid_sequence
MNGEAICSALPTIPYHKLADLRYLSRGASGTVSSARHADWRVQVAVKHLHIHTPLLDSERKDVLREAEILHKARFSYILPILGICNEPEFLGIVTEYMPNGSLNELLHRKTEYPDVAWPLRFRILHEIALGVNYLHNMTPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSSKSAPEGGTIIYMPPENYEPGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVINEESLPYDIPHRARMISLIESGWAQNPDERPSFLKCLIELEPVLRTFEEITFLEAVIQLKKTKLQSVSSAIHLCDKKKMELSLNIPVNHGPQEESCGSSQLHENSGSPETSRSLPAPQDNDFLSRKAQDCYFMKLHHCPGNHSWDSTISGSQRAAFCDHKTTPCSSAIINPLSTAGNSERLQPGIAQQWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGLQPYPEILVVSRSPSLNLLQNKSM
uniprot
proteins
ec_number
2.7.10.2
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
function
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). {ECO:0000269|PubMed:14638696, ECO:0000269|PubMed:17054981, ECO:0000269|PubMed:17562858, ECO:0000269|PubMed:18079694, ECO:0000269|PubMed:21123652, ECO:0000269|PubMed:21887730, ECO:0000269|PubMed:22607974, ECO:0000269|PubMed:26646181, ECO:0000269|PubMed:28545134, ECO:0000269|PubMed:28656966, ECO:0000269|PubMed:29452636, ECO:0000269|PubMed:30026309, ECO:0000269|PubMed:30279485, ECO:0000269|PubMed:30478312, ECO:0000269|PubMed:9575181, ECO:0000269|PubMed:9642260}.
uniprot
proteins
mass_dalton
61195
uniprot
proteins
mutagenesis
MUTAGEN 47; /note="K->A: Abolishes protein-kinase activity without preventing ability to activate NF-kappa-B downstream of NOD2."; /evidence="ECO:0000269|PubMed:28545134, ECO:0000269|PubMed:29452636, ECO:0000269|PubMed:30026309, ECO:0000269|PubMed:9575181, ECO:0000269|PubMed:9642260"; MUTAGEN 47; /note="K->M: Abolishes protein-kinase activity. Reduces FAS-mediated apoptosis."; /evidence="ECO:0000269|PubMed:27830463, ECO:0000269|PubMed:9575181, ECO:0000269|PubMed:9642260"; MUTAGEN 95; /note="T->W: Abolished ability to activate NF-kappa-B downstream of NOD2."; /evidence="ECO:0000269|PubMed:30026309"; MUTAGEN 146; /note="D->N: Abolishes protein-kinase activity without preventing ability to activate NF-kappa-B downstream of NOD2."; /evidence="ECO:0000269|PubMed:28545134, ECO:0000269|PubMed:29452636, ECO:0000269|PubMed:30026309, ECO:0000269|PubMed:9705938"; MUTAGEN 176; /note="S->A: Decreased phosphorylation and activation. Abolished phosphorylation by LRRK2."; /evidence="ECO:0000269|PubMed:27830463"; MUTAGEN 209; /note="K->R: Decreased polyubiquitination."; /evidence="ECO:0000269|PubMed:18079694"; MUTAGEN 381; /note="Y->A: Prevents phosphorylation. Reduces serine and threonine phosphorylation of ARHGEF2."; /evidence="ECO:0000269|PubMed:21887730"; MUTAGEN 410; /note="K->R: Reduced ubiquitination by XIAP and activation of NF-kappa-B; when associated with R-538."; /evidence="ECO:0000269|PubMed:29452636"; MUTAGEN 437; /note="Q->E: Decreased interaction with NGFR."; /evidence="ECO:0000269|PubMed:26646181"; MUTAGEN 444; /note="R->E: Abolishes interaction with NOD1. Abolished activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:17054981, ECO:0000269|PubMed:30478312"; MUTAGEN 445; /note="E->R: Strongly decreased activation of NF-kappa-B. Does not affect activation of NF-kappa-B; when associated with E-458."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 449; /note="N->D: Strongly decreased activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 450; /note="Q->K: Increased activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30279485"; MUTAGEN 452; /note="T->K: Impaired interaction with NOD2 and decreased homooligomerization and ability to transmit NOD2 signaling."; /evidence="ECO:0000269|PubMed:30279485"; MUTAGEN 453; /note="E->K: Decreased homooligomerization and ability to transmit NOD2 signaling."; /evidence="ECO:0000269|PubMed:30279485"; MUTAGEN 455; /note="C->S: Decreased homooligomerization and ability to transmit NOD2 signaling."; /evidence="ECO:0000269|PubMed:30279485"; MUTAGEN 458; /note="Q->E: Strongly decreased activation of NF-kappa-B. Does not affect activation of NF-kappa-B; when associated with R-445."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 461; /note="D->R: Abolished activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 467; /note="D->R: Decreased interaction with NGFR."; /evidence="ECO:0000269|PubMed:26646181"; MUTAGEN 470; /note="M->A,K: Decreased homooligomerization and ability to transmit NOD2 signaling."; /evidence="ECO:0000269|PubMed:30279485"; MUTAGEN 471; /note="K->D: Abolished activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 471; /note="K->E: Decreased interaction with NGFR."; /evidence="ECO:0000269|PubMed:26646181"; MUTAGEN 472; /note="E->R: Abolished activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 474; /note="Y->F: Decreases interaction with NOD2."; /evidence="ECO:0000269|PubMed:21123652"; MUTAGEN 474; /note="Y->R: Abolished activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 475; /note="E->R: Abolished activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 483; /note="R->D: Abolished activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 483; /note="R->E: Abolishes interaction with NOD1."; /evidence="ECO:0000269|PubMed:17054981"; MUTAGEN 488; /note="R->E: Abolishes interaction with NOD1. Abolished activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:17054981, ECO:0000269|PubMed:30478312"; MUTAGEN 492; /note="D->K: Abolished activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 496; /note="I->A: Decreased interaction with NGFR."; /evidence="ECO:0000269|PubMed:26646181"; MUTAGEN 497; /note="Q->A,K: Increased activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30279485"; MUTAGEN 497; /note="Q->E: Strongly decreased activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 500; /note="E->R: Decreased interaction with NGFR."; /evidence="ECO:0000269|PubMed:26646181"; MUTAGEN 503; /note="K->R: Abolished ubiquitination by ZNRF4."; /evidence="ECO:0000269|PubMed:28656966"; MUTAGEN 513; /note="K->E: Reduced formation of filaments and activation of NF-kappa-B."; /evidence="ECO:0000269|PubMed:30478312"; MUTAGEN 528; /note="R->E: Decreased interaction with NGFR."; /evidence="ECO:0000269|PubMed:26646181"; MUTAGEN 538; /note="K->R: Reduced ubiquitination by XIAP and activation of NF-kappa-B; when associated with R-410."; /evidence="ECO:0000269|PubMed:30478312
uniprot
proteins
post_translational_modification
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 recruitment 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). {ECO:0000250|UniProtKB:P58801, ECO:0000269|PubMed:18079694, ECO:0000269|PubMed:19464198, ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:21931591, ECO:0000269|PubMed:22607974, ECO:0000269|PubMed:23806334, ECO:0000269|PubMed:28656966, ECO:0000269|PubMed:29452636, ECO:0000269|PubMed:30026309, ECO:0000269|PubMed:36221902}.; 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). {ECO:0000269|PubMed:16824733, ECO:0000269|PubMed:21123652, ECO:0000269|PubMed:21887730, ECO:0000269|PubMed:27830463, ECO:0000269|PubMed:28545134, ECO:0000269|PubMed:29452636}.; 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). {ECO:0000269|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. {ECO:0000269|PubMed:22520462}.
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
TKL Ser/Thr protein kinase family
uniprot
proteins
pubmed
12975309
uniprot
proteins
pubmed
14638696
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15044951
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16421571
uniprot
proteins
pubmed
16824733
uniprot
proteins
pubmed
17054981
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17355968
uniprot
proteins
pubmed
17562858
uniprot
proteins
pubmed
18079694
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
18775659
uniprot
proteins
pubmed
19369195
uniprot
proteins
pubmed
19464198
uniprot
proteins
pubmed
19592251
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
21123652
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21887730
uniprot
proteins
pubmed
21931591
uniprot
proteins
pubmed
22520462
uniprot
proteins
pubmed
22607974
uniprot
proteins
pubmed
22672233
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23806334
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
26646181
uniprot
proteins
pubmed
27812135
uniprot
proteins
pubmed
27830463
uniprot
proteins
pubmed
28436939
uniprot
proteins
pubmed
28545134
uniprot
proteins
pubmed
28656966
uniprot
proteins
pubmed
29452636
uniprot
proteins
pubmed
30026309
uniprot
proteins
pubmed
30279485
uniprot
proteins
pubmed
30478312
uniprot
proteins
pubmed
36221902
uniprot
proteins
pubmed
9575181
uniprot
proteins
pubmed
9642260
uniprot
proteins
pubmed
9705938
uniprot
proteins
sequence_length
540
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21887730}. Cell membrane {ECO:0000269|PubMed:17355968}; Peripheral membrane protein {ECO:0000305|PubMed:17355968}. Endoplasmic reticulum {ECO:0000269|PubMed:28656966}. Note=Recruited to the cell membrane by NOD2 following stimulation by bacterial peptidoglycans. {ECO:0000269|PubMed:17355968}.
uniprot
proteins