IRAK-M Is a Novel Member of the Pelle/Interleukin-1 Receptor-associated Kinase (IRAK) Family

The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family. The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family. interleukin-1 receptor Toll like receptor lipopolysaccharide IL-1R-associated kinase nuclear factor-κB tumor necrosis factor luciferase Rous sarcoma virus β-galactosidase 12-O-tetradecanoylphorbol-13-acetate TNF receptor-associated factor The Toll/IL-1R1receptor family consists of a large number of transmembrane proteins with conserved intracellular domains. Structural distinctions in the extracellular domains of these proteins divide this superfamily into two subgroups: the Toll-like receptors (TLRs) with leucine-rich repeats and IL-1R-related proteins with immunoglobulin-like motifs (1; for review, see Refs. 2Belvin M.P. Anderson K.V. Annu. Rev. Cell Dev. Biol. 1996; 12: 393-416Crossref PubMed Scopus (671) Google Scholar and 3Medzhitov R. Janeway Jr., C.A. Curr. Opin. Immunol. 1998; 10: 12-15Crossref PubMed Scopus (273) Google Scholar). All members of the Toll/IL-1R family with known functions are involved in host defense. For example, the proinflammatory and immune regulatory cytokines IL-1 and IL-18 signal through members of the IL-1R-related protein subfamily (4, 5; for review, see Refs. 6Dinarello C.A. Novick D. Puren A.J. Fantuzzi G. Shapiro L. Muhl H. Yoon D.Y. Reznikov L.L. Kim S.H. Rubinstein M. J. Leukocyte Biol. 1998; 63: 658-664Crossref PubMed Scopus (331) Google Scholar and 7O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (495) Google Scholar), whereas TLR-2 and TLR-4 have been shown recently to mediate cellular response to bacterial lipopolysaccharide (LPS) (8Du X. Thompson P. Chan E.K.L. Ledesma J. Roe B. Clifton S. Vogel S.N. Beutler B. Blood Cells Mol. Dis. 1998; 24: 340-355Crossref PubMed Scopus (297) Google Scholar, 9Kirschning K.J. Wesche H. Ayres T.M. Rothe M. J. Exp. Med. 1998; 188: 2091-2097Crossref PubMed Scopus (654) Google Scholar, 10Medzhitov R. Preston-Hurlburt P. Janeway Jr., C.A. Nature. 1997; 388: 394-397Crossref PubMed Scopus (4379) Google Scholar, 11Poltorak A. He X. Smirnova I. Liu M.Y. Van Huffel C. Du X. Birdwell D. Alejos E. Silva M. Galanos C. Freudenberg M. Ricciardi-Castagnoli P. Layton B. Beutler B. Science. 1998; 282: 2085-2088Crossref PubMed Scopus (6382) Google Scholar, 12Yang R.B. Mark M.R. Gray A. Huang A. Xie M.H. Zhang M. Goddard A. Wood W.I. Gurney A.L. Godowski P.J. Nature. 1998; 395: 284-288Crossref PubMed Scopus (1098) Google Scholar).The signal transduction pathways initiated by Toll/IL-1R family members ultimately lead to the activation of members of the rel and AP-1 family of transcription factors (for review, see Refs. 2Belvin M.P. Anderson K.V. Annu. Rev. Cell Dev. Biol. 1996; 12: 393-416Crossref PubMed Scopus (671) Google Scholar, 3Medzhitov R. Janeway Jr., C.A. Curr. Opin. Immunol. 1998; 10: 12-15Crossref PubMed Scopus (273) Google Scholar, 7O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (495) Google Scholar, and 13Dinarello C.A. Blood. 1996; 87: 2095-2147Crossref PubMed Google Scholar). The receptor proximal signaling events of the proinflammatory cytokine IL-1 have been studied in detail. The first signaling event for IL-1 is the ligand-induced complex formation of IL-1RI and IL-1RAcP (14Greenfeder S.A. Nunes P. Kwee L. Labow M. Chizzonite R.A. Ju G. J. Biol. Chem. 1995; 270: 13757-13765Abstract Full Text Full Text PDF PubMed Scopus (557) Google Scholar, 15Huang J. Gao X. Li S. Cao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12829-12832Crossref PubMed Scopus (194) Google Scholar, 16Korherr C. Hofmeister R. Wesche H. Falk W. Eur. J. Immunol. 1997; 27: 262-267Crossref PubMed Scopus (153) Google Scholar, 17Wesche H. Korherr C. Kracht M. Falk W. Resch K. Martin M.U. J. Biol. Chem. 1997; 272: 7727-7731Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). The adaptor protein MyD88 is next recruited to this complex (18Lord K.A. Hoffman-Liebermann B. Liebermann D.A. Oncogene. 1990; 5: 1095-1097PubMed Google Scholar, 19Muzio M. Ni J. Feng P. Dixit V.M. Science. 1997; 278: 1612-1615Crossref PubMed Scopus (973) Google Scholar, 20Wesche H. Henzel W.J. Shillinglaw W. Li S. Cao Z. Immunity. 1997; 7: 837-847Abstract Full Text Full Text PDF PubMed Scopus (914) Google Scholar), which in turn enables the association of the IL-1R-associated kinase (IRAK) (21Cao Z. Henzel W.J. Gao X. Science. 1996; 271: 1128-1131Crossref PubMed Scopus (766) Google Scholar, 22Croston G.E. Cao Z. Goeddel D.V. J. Biol. Chem. 1995; 270: 16514-16517Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 23Martin M. Bol G.F. Eriksson A. Resch K. Brigelius-Flohe R. Eur. J. Immunol. 1994; 24: 1566-1571Crossref PubMed Scopus (80) Google Scholar). IRAK gets highly phosphorylated (21Cao Z. Henzel W.J. Gao X. Science. 1996; 271: 1128-1131Crossref PubMed Scopus (766) Google Scholar, 24Yamin T.-T. Miller D.K. J. Biol. Chem. 1997; 272: 21540-21547Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar), leaves the receptor complex, and interacts with TRAF6 (25Cao Z. Xiong J. Takeuchi M. Kurama T. Goeddel D.V. Nature. 1996; 383: 443-446Crossref PubMed Scopus (1111) Google Scholar). The IRAK-TRAF6 interaction triggers kinase cascades that lead to the activation of IκB kinases and c-Jun NH2-terminal kinase, which phosphorylate IκB and c-Jun, respectively (for review, see Refs. 7O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (495) Google Scholar, 26Baeuerle P.A. Curr. Biol. 1998; 8: R19-R22Abstract Full Text Full Text PDF PubMed Google Scholar, and 27Barnes P.J. Karin M. N. Engl. J. Med. 1997; 336: 1066-1071Crossref PubMed Scopus (4247) Google Scholar).Accumulating evidence indicates that several components of the IL-1 pathway are also utilized by other members of the Toll/IL-1R family. TLR-4 has been shown to interact with MyD88, IRAK, and TRAF6 upon overexpression (28Medzhitov R. Preston-Hurlburt P. Kopp E. Stadlen A. Chen C. Ghosh S. Janeway Jr., C.A. Mol. Cell. 1998; 2: 253-258Abstract Full Text Full Text PDF PubMed Scopus (1290) Google Scholar, 29Muzio M. Natoli G. Saccani S. Levrero M. Mantovani A. J. Exp. Med. 1998; 187: 2097-2101Crossref PubMed Scopus (525) Google Scholar). Dominant of MyD88 and TRAF6 can activation by TLR-2 K.J. Wesche H. Ayres T.M. Rothe M. J. Exp. Med. 1998; 188: 2091-2097Crossref PubMed Scopus (654) Google as as activation by TLR-4 overexpression (28Medzhitov R. Preston-Hurlburt P. Kopp E. Stadlen A. Chen C. Ghosh S. Janeway Jr., C.A. Mol. Cell. 1998; 2: 253-258Abstract Full Text Full Text PDF PubMed Scopus (1290) Google Scholar, 29Muzio M. Natoli G. Saccani S. Levrero M. Mantovani A. J. Exp. Med. 1998; 187: 2097-2101Crossref PubMed Scopus (525) Google Scholar). In addition, IL-18 IRAK and interaction with TRAF6 H. Takeuchi M. T. N. M. H. M. 1998; PubMed Scopus Google Scholar, D. K. A. E. T. S. R. A. Immunity. 1997; 7: Full Text Full Text PDF PubMed Scopus Google Scholar). evidence IL-1 signaling components in the IL-18 pathway was by the that of the in in a of response to IL-1 and IL-18 T. K. M. H. M. K. S. Immunity. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar).The of IRAK in cytokine signaling is also by show and c-Jun NH2-terminal kinase IL-1 P. K. S.A. P.A. C.A. J. Exp. Med. 1998; 187: PubMed Scopus Google Scholar). IRAK are also in and in of TNF and M. T. J. Cao Z. S.A. J. Immunol. Scholar). the IRAK of in response to IL-18 M. T. J. Cao Z. S.A. J. Immunol. Scholar). in contrast to the of the MyD88 IL-1 and IL-18 in of the the of a in molecule designated IRAK-2 has been in a M. Ni J. Feng P. Dixit V.M. Science. 1997; 278: 1612-1615Crossref PubMed Scopus (973) Google Scholar). IRAK-2 is to interact with other IL-1 signal and upon overexpression in 293 we report the identification and characterization of a novel IRAK-like molecule that has and with other members of the IRAK family. cell we evidence that IRAK-2 and the IRAK-like molecule can in signal transduction by the Toll/IL-1R receptor of the Toll/IL-1R family of transmembrane receptors in immune R. Janeway Jr., C.A. Curr. Opin. Immunol. 1998; 10: 12-15Crossref PubMed Scopus (273) Google Scholar, K. S. T. S. M. T. T. H. M. T. M. H. M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, 9Kirschning K.J. Wesche H. Ayres T.M. Rothe M. J. Exp. Med. 1998; 188: 2091-2097Crossref PubMed Scopus (654) Google Scholar, 11Poltorak A. He X. Smirnova I. Liu M.Y. Van Huffel C. Du X. Birdwell D. Alejos E. Silva M. Galanos C. Freudenberg M. Ricciardi-Castagnoli P. Layton B. Beutler B. Science. 1998; 282: 2085-2088Crossref PubMed Scopus (6382) Google Scholar, 12Yang R.B. Mark M.R. Gray A. Huang A. Xie M.H. Zhang M. Goddard A. Wood W.I. Gurney A.L. Godowski P.J. Nature. 1998; 395: 284-288Crossref PubMed Scopus (1098) Google Scholar, 13Dinarello C.A. Blood. 1996; 87: 2095-2147Crossref PubMed Google Scholar). by and members of this receptor family intracellular signal to cellular response the In this we for the first time evidence for the of IRAK in The cell line to to IL-1 as as to and this can by IRAK proteins into the that the IL-1 intracellular signaling to a of receptors that with the IL-1 that and cells IL-1 and IL-18 response P. K. S.A. P.A. C.A. J. Exp. Med. 1998; 187: PubMed Scopus Google Scholar, M. T. J. Cao Z. S.A. J. Immunol. the of with functions in The for are IRAK-2 and which in protein as as with IRAK. for this the that IRAK-2 IRAK-M reconstitute IL-1 and in the 293 in with the of IRAK-2 and IRAK-M as signaling with functions to of IRAK, response to IL-1 P. K. S.A. P.A. C.A. J. Exp. Med. 1998; 187: PubMed Scopus Google Scholar), whereas the IL-1 and response is in 293 which IRAK-M and of IRAK-like proteins are to in In contrast to IRAK and IRAK-2, is in and cell the of IRAK-M is to cells of the and is a cell of that IRAK the other IRAK-like proteins is which is in IRAK-M and IRAK-M and IRAK-2 are to and in the of IRAK. that autophosphorylation the kinase activity, is that the of IRAK in signal transduction is In IRAK autophosphorylation is only IL-1 the that the phosphorylated of IRAK is to to MyD88, which IRAK to the receptor complex H. Henzel W.J. Shillinglaw W. Li S. Cao Z. Immunity. 1997; 7: 837-847Abstract Full Text Full Text PDF PubMed Scopus (914) Google Scholar), we that the of IRAK the receptor complex and interaction with this the of the IRAK kinase in signaling in of protein which in a of IRAK. with this of IRAK proteins in upon overexpression in 293 with a the of IRAK kinase to IL-1 signaling cytokine this IRAK is by T.-T. Miller D.K. J. Biol. Chem. 1997; 272: 21540-21547Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). of the of the IL-1 response in cells of the IRAK the of IRAK to these IRAK-2 and IRAK-M have autophosphorylation the can phosphorylated in the of IRAK the that the of a in the IRAK-M IRAK-2 into a for IRAK, is to that IRAK IRAK-2 and the kinase of these the IRAK-2 and IRAK-M which are phosphorylated by IRAK in with to this that IRAK is and the other two IRAK-like proteins IL-1 and in Although we that IRAK-M and IRAK-2 mainly in the signaling of other our the that IRAK the signal IRAK-2 and IRAK-M can with IRAK, they to the cytokine by a this the of IRAK-like the of the response of a cell to a of cytokines as The Toll/IL-1R1receptor family consists of a large number of transmembrane proteins with conserved intracellular domains. Structural distinctions in the extracellular domains of these proteins divide this superfamily into two subgroups: the Toll-like receptors (TLRs) with leucine-rich repeats and IL-1R-related proteins with immunoglobulin-like motifs (1; for review, see Refs. 2Belvin M.P. Anderson K.V. Annu. Rev. Cell Dev. Biol. 1996; 12: 393-416Crossref PubMed Scopus (671) Google Scholar and 3Medzhitov R. Janeway Jr., C.A. Curr. Opin. Immunol. 1998; 10: 12-15Crossref PubMed Scopus (273) Google Scholar). All members of the Toll/IL-1R family with known functions are involved in host defense. For example, the proinflammatory and immune regulatory cytokines IL-1 and IL-18 signal through members of the IL-1R-related protein subfamily (4, 5; for review, see Refs. 6Dinarello C.A. Novick D. Puren A.J. Fantuzzi G. Shapiro L. Muhl H. Yoon D.Y. Reznikov L.L. Kim S.H. Rubinstein M. J. Leukocyte Biol. 1998; 63: 658-664Crossref PubMed Scopus (331) Google Scholar and 7O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (495) Google Scholar), whereas TLR-2 and TLR-4 have been shown recently to mediate cellular response to bacterial lipopolysaccharide (LPS) (8Du X. Thompson P. Chan E.K.L. Ledesma J. Roe B. Clifton S. Vogel S.N. Beutler B. Blood Cells Mol. Dis. 1998; 24: 340-355Crossref PubMed Scopus (297) Google Scholar, 9Kirschning K.J. Wesche H. Ayres T.M. Rothe M. J. Exp. Med. 1998; 188: 2091-2097Crossref PubMed Scopus (654) Google Scholar, 10Medzhitov R. Preston-Hurlburt P. Janeway Jr., C.A. Nature. 1997; 388: 394-397Crossref PubMed Scopus (4379) Google Scholar, 11Poltorak A. He X. Smirnova I. Liu M.Y. Van Huffel C. Du X. Birdwell D. Alejos E. Silva M. Galanos C. Freudenberg M. Ricciardi-Castagnoli P. Layton B. Beutler B. Science. 1998; 282: 2085-2088Crossref PubMed Scopus (6382) Google Scholar, 12Yang R.B. Mark M.R. Gray A. Huang A. Xie M.H. Zhang M. Goddard A. Wood W.I. Gurney A.L. Godowski P.J. Nature. 1998; 395: 284-288Crossref PubMed Scopus (1098) Google Scholar). The signal transduction pathways initiated by Toll/IL-1R family members ultimately lead to the activation of members of the rel and AP-1 family of transcription factors (for review, see Refs. 2Belvin M.P. Anderson K.V. Annu. Rev. Cell Dev. Biol. 1996; 12: 393-416Crossref PubMed Scopus (671) Google Scholar, 3Medzhitov R. Janeway Jr., C.A. Curr. Opin. Immunol. 1998; 10: 12-15Crossref PubMed Scopus (273) Google Scholar, 7O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (495) Google Scholar, and 13Dinarello C.A. Blood. 1996; 87: 2095-2147Crossref PubMed Google Scholar). The receptor proximal signaling events of the proinflammatory cytokine IL-1 have been studied in detail. The first signaling event for IL-1 is the ligand-induced complex formation of IL-1RI and IL-1RAcP (14Greenfeder S.A. Nunes P. Kwee L. Labow M. Chizzonite R.A. Ju G. J. Biol. Chem. 1995; 270: 13757-13765Abstract Full Text Full Text PDF PubMed Scopus (557) Google Scholar, 15Huang J. Gao X. Li S. Cao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12829-12832Crossref PubMed Scopus (194) Google Scholar, 16Korherr C. Hofmeister R. Wesche H. Falk W. Eur. J. Immunol. 1997; 27: 262-267Crossref PubMed Scopus (153) Google Scholar, 17Wesche H. Korherr C. Kracht M. Falk W. Resch K. Martin M.U. J. Biol. Chem. 1997; 272: 7727-7731Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). The adaptor protein MyD88 is next recruited to this complex (18Lord K.A. Hoffman-Liebermann B. Liebermann D.A. Oncogene. 1990; 5: 1095-1097PubMed Google Scholar, 19Muzio M. Ni J. Feng P. Dixit V.M. Science. 1997; 278: 1612-1615Crossref PubMed Scopus (973) Google Scholar, 20Wesche H. Henzel W.J. Shillinglaw W. Li S. Cao Z. Immunity. 1997; 7: 837-847Abstract Full Text Full Text PDF PubMed Scopus (914) Google Scholar), which in turn enables the association of the IL-1R-associated kinase (IRAK) (21Cao Z. Henzel W.J. Gao X. Science. 1996; 271: 1128-1131Crossref PubMed Scopus (766) Google Scholar, 22Croston G.E. Cao Z. Goeddel D.V. J. Biol. Chem. 1995; 270: 16514-16517Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 23Martin M. Bol G.F. Eriksson A. Resch K. Brigelius-Flohe R. Eur. J. Immunol. 1994; 24: 1566-1571Crossref PubMed Scopus (80) Google Scholar). IRAK gets highly phosphorylated (21Cao Z. Henzel W.J. Gao X. Science. 1996; 271: 1128-1131Crossref PubMed Scopus (766) Google Scholar, 24Yamin T.-T. Miller D.K. J. Biol. Chem. 1997; 272: 21540-21547Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar), leaves the receptor complex, and interacts with TRAF6 (25Cao Z. Xiong J. Takeuchi M. Kurama T. Goeddel D.V. Nature. 1996; 383: 443-446Crossref PubMed Scopus (1111) Google Scholar). The IRAK-TRAF6 interaction triggers kinase cascades that lead to the activation of IκB kinases and c-Jun NH2-terminal kinase, which phosphorylate IκB and c-Jun, respectively (for review, see Refs. 7O'Neill L.A. Greene C. J. Leukocyte Biol. 1998; 63: 650-657Crossref PubMed Scopus (495) Google Scholar, 26Baeuerle P.A. Curr. Biol. 1998; 8: R19-R22Abstract Full Text Full Text PDF PubMed Google Scholar, and 27Barnes P.J. Karin M. N. Engl. J. Med. 1997; 336: 1066-1071Crossref PubMed Scopus (4247) Google Scholar). evidence indicates that several components of the IL-1 pathway are also utilized by other members of the Toll/IL-1R family. TLR-4 has been shown to interact with MyD88, IRAK, and TRAF6 upon overexpression (28Medzhitov R. Preston-Hurlburt P. Kopp E. Stadlen A. Chen C. Ghosh S. Janeway Jr., C.A. Mol. Cell. 1998; 2: 253-258Abstract Full Text Full Text PDF PubMed Scopus (1290) Google Scholar, 29Muzio M. Natoli G. Saccani S. Levrero M. Mantovani A. J. Exp. Med. 1998; 187: 2097-2101Crossref PubMed Scopus (525) Google Scholar). Dominant of MyD88 and TRAF6 can activation by TLR-2 K.J. Wesche H. Ayres T.M. Rothe M. J. Exp. Med. 1998; 188: 2091-2097Crossref PubMed Scopus (654) Google as as activation by TLR-4 overexpression (28Medzhitov R. Preston-Hurlburt P. Kopp E. Stadlen A. Chen C. Ghosh S. Janeway Jr., C.A. Mol. Cell. 1998; 2: 253-258Abstract Full Text Full Text PDF PubMed Scopus (1290) Google Scholar, 29Muzio M. Natoli G. Saccani S. Levrero M. Mantovani A. J. Exp. Med. 1998; 187: 2097-2101Crossref PubMed Scopus (525) Google Scholar). In addition, IL-18 IRAK and interaction with TRAF6 H. Takeuchi M. T. N. M. H. M. 1998; PubMed Scopus Google Scholar, D. K. A. E. T. S. R. A. Immunity. 1997; 7: Full Text Full Text PDF PubMed Scopus Google Scholar). evidence IL-1 signaling components in the IL-18 pathway was by the that of the in in a of response to IL-1 and IL-18 T. K. M. H. M. K. S. Immunity. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The of IRAK in cytokine signaling is also by show and c-Jun NH2-terminal kinase IL-1 P. K. S.A. P.A. C.A. J. Exp. Med. 1998; 187: PubMed Scopus Google Scholar). IRAK are also in and in of TNF and M. T. J. Cao Z. S.A. J. Immunol. Scholar). the IRAK of in response to IL-18 M. T. J. Cao Z. S.A. J. Immunol. Scholar). in contrast to the of the MyD88 IL-1 and IL-18 in of the the of a in molecule designated IRAK-2 has been in a M. Ni J. Feng P. Dixit V.M. Science. 1997; 278: 1612-1615Crossref PubMed Scopus (973) Google Scholar). IRAK-2 is to interact with other IL-1 signal and upon overexpression in 293 we report the identification and characterization of a novel IRAK-like molecule that has and with other members of the IRAK family. cell we evidence that IRAK-2 and the IRAK-like molecule can in signal transduction by the Toll/IL-1R receptor family. of the Toll/IL-1R family of transmembrane receptors in immune R. Janeway Jr., C.A. Curr. Opin. Immunol. 1998; 10: 12-15Crossref PubMed Scopus (273) Google Scholar, K. S. T. S. M. T. T. H. M. T. M. H. M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, 9Kirschning K.J. Wesche H. Ayres T.M. Rothe M. J. Exp. Med. 1998; 188: 2091-2097Crossref PubMed Scopus (654) Google Scholar, 11Poltorak A. He X. Smirnova I. Liu M.Y. Van Huffel C. Du X. Birdwell D. Alejos E. Silva M. Galanos C. Freudenberg M. Ricciardi-Castagnoli P. Layton B. Beutler B. Science. 1998; 282: 2085-2088Crossref PubMed Scopus (6382) Google Scholar, 12Yang R.B. Mark M.R. Gray A. Huang A. Xie M.H. Zhang M. Goddard A. Wood W.I. Gurney A.L. Godowski P.J. Nature. 1998; 395: 284-288Crossref PubMed Scopus (1098) Google Scholar, 13Dinarello C.A. Blood. 1996; 87: 2095-2147Crossref PubMed Google Scholar). by and members of this receptor family intracellular signal to cellular response the In this we for the first time evidence for the of IRAK in The cell line to to IL-1 as as to and this can by IRAK proteins into the that the IL-1 intracellular signaling to a of receptors that with the IL-1 that and cells IL-1 and IL-18 response P. K. S.A. P.A. C.A. J. Exp. Med. 1998; 187: PubMed Scopus Google Scholar, M. T. J. Cao Z. S.A. J. Immunol. the of with functions in The for are IRAK-2 and which in protein as as with IRAK. for this the that IRAK-2 IRAK-M reconstitute IL-1 and in the 293 in with the of IRAK-2 and IRAK-M as signaling with functions to of IRAK, response to IL-1 P. K. S.A. P.A. C.A. J. Exp. Med. 1998; 187: PubMed Scopus Google Scholar), whereas the IL-1 and response is in 293 which IRAK-M and of IRAK-like proteins are to in In contrast to IRAK and IRAK-2, is in and cell the of IRAK-M is to cells of the and is a cell of that IRAK the other IRAK-like proteins is which is in IRAK-M and IRAK-M and IRAK-2 are to and in the of IRAK. that autophosphorylation the kinase activity, is that the of IRAK in signal transduction is In IRAK autophosphorylation is only IL-1 the that the phosphorylated of IRAK is to to MyD88, which IRAK to the receptor complex H. Henzel W.J. Shillinglaw W. Li S. Cao Z. Immunity. 1997; 7: 837-847Abstract Full Text Full Text PDF PubMed Scopus (914) Google Scholar), we that the of IRAK the receptor complex and interaction with this the of the IRAK kinase in signaling in of protein which in a of IRAK. with this of IRAK proteins in upon overexpression in 293 with a the of IRAK kinase to IL-1 signaling cytokine this IRAK is by T.-T. Miller D.K. J. Biol. Chem. 1997; 272: 21540-21547Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). of the of the IL-1 response in cells of the IRAK the of IRAK to these IRAK-2 and IRAK-M have autophosphorylation the can phosphorylated in the of IRAK the that the of a in the IRAK-M IRAK-2 into a for IRAK, is to that IRAK IRAK-2 and the kinase of these the IRAK-2 and IRAK-M which are phosphorylated by IRAK in with to this that IRAK is and the other two IRAK-like proteins IL-1 and in Although we that IRAK-M and IRAK-2 mainly in the signaling of other our the that IRAK the signal IRAK-2 and IRAK-M can with IRAK, they to the cytokine by a this the of IRAK-like the of the response of a cell to a of cytokines as of the Toll/IL-1R family of transmembrane receptors in immune R. Janeway Jr., C.A. Curr. Opin. Immunol. 1998; 10: 12-15Crossref PubMed Scopus (273) Google Scholar, K. S. T. S. M. T. T. H. M. T. M. H. M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, 9Kirschning K.J. Wesche H. Ayres T.M. Rothe M. J. Exp. Med. 1998; 188: 2091-2097Crossref PubMed Scopus (654) Google Scholar, 11Poltorak A. He X. Smirnova I. Liu M.Y. Van Huffel C. Du X. Birdwell D. Alejos E. Silva M. Galanos C. Freudenberg M. Ricciardi-Castagnoli P. Layton B. Beutler B. Science. 1998; 282: 2085-2088Crossref PubMed Scopus (6382) Google Scholar, 12Yang R.B. Mark M.R. Gray A. Huang A. Xie M.H. Zhang M. Goddard A. Wood W.I. Gurney A.L. Godowski P.J. Nature. 1998; 395: 284-288Crossref PubMed Scopus (1098) Google Scholar, 13Dinarello C.A. Blood. 1996; 87: 2095-2147Crossref PubMed Google Scholar). by and members of this receptor family intracellular signal to cellular response the In this we for the first time evidence for the of IRAK in The cell line to to IL-1 as as to and this can by IRAK proteins into the that the IL-1 intracellular signaling to a of receptors that with the IL-1 The that and cells IL-1 and IL-18 response P. K. S.A. P.A. C.A. J. Exp. Med. 1998; 187: PubMed Scopus Google Scholar, M. T. J. Cao Z. S.A. J. Immunol. the of with functions in The for are IRAK-2 and which in protein as as with IRAK. for this the that IRAK-2 IRAK-M reconstitute IL-1 and in the 293 in with the of IRAK-2 and IRAK-M as signaling with functions to of IRAK, response to IL-1 P. K. S.A. P.A. C.A. J. Exp. 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