IRAK3_MOUSE
ID IRAK3_MOUSE Reviewed; 609 AA.
AC Q8K4B2; Q8C7U8; Q8CE40; Q8K1S8;
DT 09-NOV-2004, integrated into UniProtKB/Swiss-Prot.
DT 25-OCT-2004, sequence version 2.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=Interleukin-1 receptor-associated kinase 3;
DE Short=IRAK-3;
DE AltName: Full=IL-1 receptor-associated kinase M;
DE Short=IRAK-M;
DE AltName: Full=Inactive IL-1 receptor-associated kinase 3 {ECO:0000305};
GN Name=Irak3 {ECO:0000312|MGI:MGI:1921164};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1] {ECO:0000305, ECO:0000312|EMBL:AAM83393.1}
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC STRAIN=C57BL/6J {ECO:0000312|EMBL:AAM83393.1};
RC TISSUE=Macrophage {ECO:0000269|PubMed:12150927};
RX PubMed=12150927; DOI=10.1016/s0092-8674(02)00827-9;
RA Kobayashi K., Hernandez L.D., Galan J.E., Janeway C.A. Jr., Medzhitov R.,
RA Flavell R.A.;
RT "IRAK-M is a negative regulator of Toll-like receptor signaling.";
RL Cell 110:191-202(2002).
RN [2] {ECO:0000305, ECO:0000312|EMBL:CAD29448.2}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RC STRAIN=BALB/cJ {ECO:0000312|EMBL:CAD29448.2};
RC TISSUE=Macrophage {ECO:0000269|PubMed:12054681};
RX PubMed=12054681; DOI=10.1016/s0006-291x(02)00411-4;
RA Rosati O., Martin M.U.;
RT "Identification and characterization of murine IRAK-M.";
RL Biochem. Biophys. Res. Commun. 293:1472-1477(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Skin;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP FUNCTION, INTERACTION WITH PIN1, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP AND DISRUPTION PHENOTYPE.
RX PubMed=29686383; DOI=10.1038/s41467-018-03886-6;
RA Nechama M., Kwon J., Wei S., Kyi A.T., Welner R.S., Ben-Dov I.Z.,
RA Arredouani M.S., Asara J.M., Chen C.H., Tsai C.Y., Nelson K.F.,
RA Kobayashi K.S., Israel E., Zhou X.Z., Nicholson L.K., Lu K.P.;
RT "The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-
RT induced allergic airway inflammation.";
RL Nat. Commun. 9:1603-1603(2018).
CC -!- FUNCTION: Putative inactive protein kinase which regulates signaling
CC downstream of immune receptors including IL1R and Toll-like receptors
CC (PubMed:12150927, PubMed:12054681, PubMed:29686383). Inhibits
CC dissociation of IRAK1 and IRAK4 from the Toll-like receptor signaling
CC complex by either inhibiting the phosphorylation of IRAK1 and IRAK4 or
CC stabilizing the receptor complex (PubMed:12150927, PubMed:12054681).
CC Upon IL33-induced lung inflammation, positively regulates expression of
CC IL6, CSF3, CXCL2 and CCL5 mRNAs in dendritic cells (PubMed:29686383).
CC {ECO:0000269|PubMed:12054681, ECO:0000269|PubMed:12150927,
CC ECO:0000269|PubMed:29686383}.
CC -!- SUBUNIT: Monomer (By similarity). Homodimer (By similarity). May
CC interact with IRAK4 (when phosphorylated) (By similarity). Interacts
CC (when phosphorylated at Thr-110) with PIN1 (via WW domain) in response
CC to IL33-mediated (but not TLR4 ligand LPS) dendritic cell stimulation
CC (PubMed:29686383). {ECO:0000250|UniProtKB:Q9Y616,
CC ECO:0000269|PubMed:29686383}.
CC -!- INTERACTION:
CC Q8K4B2; Q8R4K2: Irak4; NbExp=7; IntAct=EBI-646179, EBI-3842721;
CC Q8K4B2; P70196: Traf6; NbExp=3; IntAct=EBI-646179, EBI-448028;
CC Q8K4B2; Q9NWZ3: IRAK4; Xeno; NbExp=4; IntAct=EBI-646179, EBI-448378;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:29686383}. Nucleus
CC {ECO:0000269|PubMed:29686383}. Note=In dendritic cells, translocates
CC into the nucleus upon IL33 stimulation. {ECO:0000269|PubMed:29686383}.
CC -!- TISSUE SPECIFICITY: Expressed in inflamed lung macrophages (at protein
CC level) (PubMed:29686383). Expressed in dendritic cells (at protein
CC level) (PubMed:29686383). Highly expressed in liver and thymus and at
CC lower levels in heart, brain, spleen and kidney (PubMed:12054681).
CC {ECO:0000269|PubMed:12054681, ECO:0000269|PubMed:29686383}.
CC -!- DOMAIN: The nucleotide binding domain binds ATP with low affinity.
CC {ECO:0000250|UniProtKB:Q9Y616}.
CC -!- DISRUPTION PHENOTYPE: In response to intranasal administration of IL33,
CC lung inflammation is reduced compared to wild-type and is associated
CC with low infiltration by inflammatory cells, especially granulocytes, a
CC severe reduction in Th2-type cytokine secretion, including Il4, Il5 and
CC Il13 in bronchial alveolar fluids, and reduced up-regulation of Il6,
CC Csf3, Cxcl2 and Ccl5 mRNAs. {ECO:0000269|PubMed:29686383}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. Pelle subfamily. {ECO:0000305}.
CC -!- CAUTION: Asn-306 is present instead of the conserved Asp which is
CC expected to be an active site residue. Low level autophosphorylation
CC activity has been reported in PubMed:12054681, while other authors
CC describe this as an inactive kinase. {ECO:0000305}.
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DR EMBL; AF461763; AAM83393.1; -; mRNA.
DR EMBL; AJ440757; CAD29448.2; -; mRNA.
DR EMBL; AK029057; BAC26270.1; -; mRNA.
DR EMBL; AK049210; BAC33612.1; -; mRNA.
DR CCDS; CCDS24204.1; -.
DR RefSeq; NP_082955.2; NM_028679.3.
DR AlphaFoldDB; Q8K4B2; -.
DR SMR; Q8K4B2; -.
DR BioGRID; 216351; 3.
DR IntAct; Q8K4B2; 19.
DR MINT; Q8K4B2; -.
DR STRING; 10090.ENSMUSP00000020448; -.
DR iPTMnet; Q8K4B2; -.
DR PhosphoSitePlus; Q8K4B2; -.
DR jPOST; Q8K4B2; -.
DR MaxQB; Q8K4B2; -.
DR PaxDb; Q8K4B2; -.
DR PRIDE; Q8K4B2; -.
DR ProteomicsDB; 267005; -.
DR Antibodypedia; 16652; 579 antibodies from 45 providers.
DR DNASU; 73914; -.
DR Ensembl; ENSMUST00000020448; ENSMUSP00000020448; ENSMUSG00000020227.
DR GeneID; 73914; -.
DR KEGG; mmu:73914; -.
DR UCSC; uc007het.1; mouse.
DR CTD; 11213; -.
DR MGI; MGI:1921164; Irak3.
DR VEuPathDB; HostDB:ENSMUSG00000020227; -.
DR eggNOG; KOG1187; Eukaryota.
DR GeneTree; ENSGT00940000161222; -.
DR HOGENOM; CLU_029530_0_0_1; -.
DR InParanoid; Q8K4B2; -.
DR OMA; QKIPFEC; -.
DR OrthoDB; 684563at2759; -.
DR PhylomeDB; Q8K4B2; -.
DR TreeFam; TF328924; -.
DR Reactome; R-MMU-9020702; Interleukin-1 signaling.
DR BioGRID-ORCS; 73914; 4 hits in 73 CRISPR screens.
DR ChiTaRS; Irak3; mouse.
DR PRO; PR:Q8K4B2; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q8K4B2; protein.
DR Bgee; ENSMUSG00000020227; Expressed in granulocyte and 89 other tissues.
DR ExpressionAtlas; Q8K4B2; baseline and differential.
DR Genevisible; Q8K4B2; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; IDA:MGI.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IDA:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; IEA:InterPro.
DR GO; GO:0001960; P:negative regulation of cytokine-mediated signaling pathway; IC:BHF-UCL.
DR GO; GO:0045824; P:negative regulation of innate immune response; IMP:BHF-UCL.
DR GO; GO:0032695; P:negative regulation of interleukin-12 production; IMP:BHF-UCL.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IMP:BHF-UCL.
DR GO; GO:0010936; P:negative regulation of macrophage cytokine production; IMP:BHF-UCL.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IMP:BHF-UCL.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISO:MGI.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IMP:BHF-UCL.
DR GO; GO:0043242; P:negative regulation of protein-containing complex disassembly; ISO:MGI.
DR GO; GO:0034122; P:negative regulation of toll-like receptor signaling pathway; IMP:BHF-UCL.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IMP:BHF-UCL.
DR GO; GO:0001819; P:positive regulation of cytokine production; IMP:UniProtKB.
DR GO; GO:0010933; P:positive regulation of macrophage tolerance induction; IMP:BHF-UCL.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:MGI.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:MGI.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0043244; P:regulation of protein-containing complex disassembly; IDA:UniProtKB.
DR GO; GO:0043330; P:response to exogenous dsRNA; IMP:BHF-UCL.
DR GO; GO:0070555; P:response to interleukin-1; ISO:MGI.
DR GO; GO:0032496; P:response to lipopolysaccharide; IMP:BHF-UCL.
DR GO; GO:0032494; P:response to peptidoglycan; IMP:BHF-UCL.
DR GO; GO:0009615; P:response to virus; IC:BHF-UCL.
DR CDD; cd08796; Death_IRAK-M; 1.
DR CDD; cd14160; PK_IRAK3; 1.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR033610; IRAK3.
DR InterPro; IPR042747; IRAK3_death.
DR InterPro; IPR042698; IRAK3_PK.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR PANTHER; PTHR24419:SF7; PTHR24419:SF7; 1.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00005; DEATH; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cytoplasm; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..609
FT /note="Interleukin-1 receptor-associated kinase 3"
FT /id="PRO_0000086034"
FT DOMAIN 41..106
FT /note="Death"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00064"
FT DOMAIN 178..463
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 184..192
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 205
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 308..311
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 324
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 110..111
FT /note="Cis/trans isomerization of proline peptide bond; by
FT PIN1; dependent on Thr-110 phosphorylation"
FT /evidence="ECO:0000250|UniProtKB:Q9Y616"
FT MOD_RES 110
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y616"
FT MOD_RES 480
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y616"
FT CONFLICT 35
FT /note="C -> W (in Ref. 1; AAM83393)"
FT /evidence="ECO:0000305"
FT CONFLICT 42
FT /note="R -> W (in Ref. 1; AAM83393)"
FT /evidence="ECO:0000305"
FT CONFLICT 62
FT /note="V -> L (in Ref. 1; AAM83393)"
FT /evidence="ECO:0000305"
FT CONFLICT 126
FT /note="P -> L (in Ref. 1; AAM83393)"
FT /evidence="ECO:0000305"
FT CONFLICT 147
FT /note="V -> M (in Ref. 1; AAM83393)"
FT /evidence="ECO:0000305"
FT CONFLICT 282
FT /note="S -> G (in Ref. 3; BAC33612)"
FT /evidence="ECO:0000305"
FT CONFLICT 282
FT /note="S -> N (in Ref. 1; AAM83393)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 609 AA; 68455 MW; A63E010C9F29D856 CRC64;
MAGRCGARGA LSPQLLLFDL PPALLGELCG ILDSCDGPLG WRGLAERLSN SWLDVRHIEK
YVNQGKSGTR ELLWSWAQKN KTIGDLLEVL QDMGHQRAIH LIINYGVSWT PSVQTHHELP
FPSFPPEVKH ACRENDPGPL EPANVTVDNV LVPEHNEKGT LQKTPISFQS ILEGTKHFHK
DFLIGEGEIF EVYRVDIRNQ AYAVKLFKQE KKMQLKKHWK RFLSELEVLL LFRHPHILEL
AAYFTETEKL CLVYPYMSNG TLFDRLQCTN GTTPLSWHVR ISVLIGIAKA IQYLHNTQPC
AVICGNVSSA NILLDDQLQP KLTDFAAAHF RPNLEQQSST INMTGGGRKH LWYMPEEYIR
QGRLSVKTDV YSFGIVIMEV LTGCKVVLDD PKHVQLRDLL MELMEKRGLD SCLSFLDRKI
PPCPRNFSAK LFSLAGRCVA TKAKLRPTMD EVLSSLESTQ PSLYFAEDPP TSLKSFRCPS
PLFLDNVPSI PVEDDENQNN HSVPPKEVLG TDRVTQKTPF ECSQSEVTFL GLDRNRGNRG
SEADCNVPSS SHEECWSPEL VAPSQDLSPT VISLGSSWEV PGHSYGSKPM EKRCSSGLFC
SEHEQSKKQ
