P58801 (RIPK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Receptor-interacting serine/threonine-protein kinase 2
EC=2.7.11.1

Alternative name(s):
Tyrosine-protein kinase RIPK2
EC=2.7.10.2

Gene names

Name:

Ripk2

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	539 AA.
Sequence status	Complete.
Protein existence	Evidence at transcript level

General annotation (Comments)

Function	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. Once recruited, autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases 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 release 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. Ref.4
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	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 and NOD2. 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 By similarity.
Subcellular location	Cytoplasm Probable.
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 By similarity.
Post-translational modification	Autophosphorylated. Autophosphorylation at Tyr-473 is necessary for effective NOD2 signaling. 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 By similarity.
Disruption phenotype	Mice show a lack of chemokine production induced by bacterial peptidoglycans. RIPK2 deficiency affects cellular signaling and cytokine responses triggered by NOD1 and NOD2 ligands, but not TLR ligands. Ref.3 Ref.4
Sequence similarities	Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Contains 1 CARD domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Adaptive immunity Apoptosis Immunity Innate immunity
Cellular component	Cytoplasm
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	I-kappaB kinase/NF-kappaB cascade Inferred from mutant phenotype Ref.4. Source: UniProtKB T cell proliferation Inferred from mutant phenotype PubMed 14638696. Source: MGI T cell receptor signaling pathway Inferred from mutant phenotype Ref.4. Source: UniProtKB adaptive immune response Inferred from mutant phenotype Ref.4. Source: UniProtKB apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cellular response to lipoteichoic acid Inferred from mutant phenotype PubMed 11894098. Source: MGI cellular response to peptidoglycan Inferred from mutant phenotype PubMed 11894098. Source: MGI defense response to Gram-positive bacterium Inferred from mutant phenotype Ref.1PubMed 11894098PubMed 18261938. Source: MGI innate immune response Inferred from mutant phenotype Ref.4. Source: UniProtKB lipopolysaccharide-mediated signaling pathway Inferred from mutant phenotype PubMed 11894098. Source: MGI nucleotide-binding oligomerization domain containing 1 signaling pathway Inferred from mutant phenotype PubMed 11894098. Source: MGI nucleotide-binding oligomerization domain containing 2 signaling pathway Inferred from mutant phenotype PubMed 11894098. Source: MGI positive regulation of ERK1 and ERK2 cascade Inferred from direct assay PubMed 18261938. Source: MGI positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from mutant phenotype Ref.1PubMed 11894098PubMed 18261938. Source: MGI positive regulation of JNK cascade Inferred from mutant phenotype Ref.1PubMed 11894098PubMed 18261938. Source: MGI positive regulation of NF-kappaB transcription factor activity Inferred from mutant phenotype PubMed 14638696. Source: MGI positive regulation of T-helper 1 cell differentiation Inferred from mutant phenotype Ref.1. Source: MGI positive regulation of T-helper 1 type immune response Inferred from mutant phenotype Ref.1. Source: MGI positive regulation of alpha-beta T cell proliferation Inferred from mutant phenotype Ref.1PubMed 11894098. Source: MGI positive regulation of apoptotic process Inferred from direct assay PubMed 14663141. Source: MGI positive regulation of chemokine production Inferred from mutant phenotype PubMed 11894098. Source: MGI positive regulation of cytokine-mediated signaling pathway Inferred from mutant phenotype Ref.1. Source: MGI positive regulation of immature T cell proliferation Inferred from mutant phenotype PubMed 11894098. Source: MGI positive regulation of interferon-gamma production Inferred from mutant phenotype Ref.1PubMed 11894098. Source: MGI positive regulation of interleukin-2 production Inferred from mutant phenotype PubMed 11894098. Source: MGI positive regulation of interleukin-6 production Inferred from mutant phenotype PubMed 11894098PubMed 18261938. Source: MGI positive regulation of protein ubiquitination Inferred from electronic annotation. Source: Compara positive regulation of tumor necrosis factor production Inferred from mutant phenotype PubMed 11894098PubMed 18261938. Source: MGI response to exogenous dsRNA Inferred from mutant phenotype PubMed 11894098. Source: MGI response to interleukin-1 Inferred from mutant phenotype PubMed 11894098. Source: MGI response to interleukin-12 Inferred from mutant phenotype Ref.1PubMed 11894098. Source: MGI response to interleukin-18 Inferred from mutant phenotype Ref.1PubMed 11894098. Source: MGI toll-like receptor 2 signaling pathway Inferred from electronic annotation. Source: Compara toll-like receptor 4 signaling pathway Inferred from mutant phenotype PubMed 11894098. Source: MGI
Cellular_component	cytosol Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW non-membrane spanning protein tyrosine kinase activity Inferred from electronic annotation. Source: EC protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 539	539	Receptor-interacting serine/threonine-protein kinase 2		PRO_0000086609
Regions
	Domain	18 – 294	277	Protein kinase
	Domain	431 – 523	93	CARD
	Nucleotide binding	24 – 32	9	ATP By similarity
Sites
	Active site	146	1	Proton acceptor By similarity
	Binding site	47	1	ATP By similarity
Amino acid modifications
	Modified residue	168	1	Phosphoserine By similarity
	Modified residue	176	1	Phosphoserine; by autocatalysis By similarity
	Modified residue	362	1	Phosphoserine By similarity
	Modified residue	392	1	Phosphoserine By similarity
	Modified residue	473	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	526	1	Phosphoserine By similarity
	Modified residue	538	1	Phosphoserine By similarity

Sequences

	Sequence		Length	Mass (Da)
	P58801 [UniParc]. Last modified May 2, 2002. Version 1. Checksum: 42951BF97CA15DFA	FASTA	539	60,400
	10 20 30 40 50 60 MNGDAICSAL PPIPYHKLAD LHYLSRGASG TVSSARHADW RVRVAVKHLH IHTPLLDSER 70 80 90 100 110 120 NDILREAEIL HKARFSYILP ILGICNEPEF LGIVTEYMPN GSLNELLHRK TEYPDIAWPL 130 140 150 160 170 180 RFRILHEIAL GVNYLHNMNP PLLHHDLKTQ NILLDNEFHV KIADFGLSKW RMMSLSQSRS 190 200 210 220 230 240 YKSAPEGGTI IYMPPENYEP GQKSRASVKH DIYSYAVIMW EVLSRKQPFE EVTNPLQIMY 250 260 270 280 290 300 SVSQGHRPDT SEENLPFDIP HRGLMISLIQ SGWAQNPDER PSFLKCLIEL EPVLRTFEDI 310 320 330 340 350 360 TFLEAVIQLK KAKIQSSSST IHLCDKKMDL SLNIPANHPP QEESCGSSLL SRNTGSPGPS 370 380 390 400 410 420 RSLSAPQDKG FLSGAPQDCS SLKAHHCPGN HSWDGIVSVP PGAAFCDRRA SSCSLAVISP 430 440 450 460 470 480 FLVEKGSERP PIGIAQQWIQ SKREAIVSQM TEACLNQSLD ALLSRDLIMK EDYELISTKP 490 500 510 520 530 TRTSKVRQLL DTSDIQGEEF AKVVVQKLKD NKQLGLQPYP EVPVLSKAPP SNFPQNKSL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Involvement of receptor-interacting protein 2 in innate and adaptive immune responses." Chin A.I., Dempsey P.W., Bruhn K., Miller J.F., Xu Y., Cheng G. Nature 416:190-194(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: C57BL/6.
[2]	"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]. Strain: 129. Tissue: Mammary gland.
[3]	"RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs." Park J.H., Kim Y.G., McDonald C., Kanneganti T.D., Hasegawa M., Body-Malapel M., Inohara N., Nunez G. J. Immunol. 178:2380-2386(2007) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[4]	"Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands." Magalhaes J.G., Lee J., Geddes K., Rubino S., Philpott D.J., Girardin S.E. Eur. J. Immunol. 41:1445-1455(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF461040 mRNA. Translation: AAL96436.1. BC069878 mRNA. Translation: AAH69878.1.
IPI	IPI00139382.
RefSeq	NP_620402.1. NM_138952.3.
UniGene	Mm.112765.
3D structure databases
ProteinModelPortal	P58801.
SMR	P58801. Positions 9-299.
ModBase	Search...
PTM databases
PhosphoSite	P58801.
Proteomic databases
PaxDb	P58801.
PRIDE	P58801.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000037035; ENSMUSP00000038833; ENSMUSG00000041135.
GeneID	192656.
KEGG	mmu:192656.
Organism-specific databases
CTD	8767.
MGI	MGI:1891456. Ripk2.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000136856.
HOVERGEN	HBG054242.
InParanoid	P58801.
KO	K08846.
OMA	PDVAWPL.
OrthoDB	EOG4VQ9NZ.
Enzyme and pathway databases
Reactome	REACT_107772. Immune System.
Gene expression databases
ArrayExpress	P58801.
Bgee	P58801.
Genevestigator	P58801.
GermOnline	ENSMUSG00000041135. Mus musculus.
Family and domain databases
Gene3D	1.10.533.10. 1 hit.
InterPro	IPR001315. CARD. IPR011029. DEATH-like_dom. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017322. Rcpt-int_Ser/Thr_kinase-2. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00619. CARD. 1 hit. PF00069. Pkinase. 1 hit. [Graphical view]
PIRSF	PIRSF037921. STPK_RIP2. 1 hit.
SMART	SM00114. CARD. 1 hit. [Graphical view]
SUPFAM	SSF47986. DEATH_like. 1 hit. SSF56112. Kinase_like. 1 hit.
PROSITE	PS50209. CARD. 1 hit. PS00107. PROTEIN_KINASE_ATP. False negative. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	371321.
SOURCE	Search...

Entry information

Entry name

RIPK2_MOUSE

Accession

Primary (citable) accession number: P58801

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 2, 2002
Last sequence update:	May 2, 2002
Last modified:	May 1, 2013
This is version 114 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program