Identification of a Novel Human Kinase Supporter of Ras (hKSR-2) That Functions as a Negative Regulator of Cot (Tpl2) Signaling

Kinase suppressor of Ras (KSR) is an integral and conserved component of the Ras signaling pathway. Although KSR is a positive regulator of the Ras/mitogen-activated protein (MAP) kinase pathway, the role of KSR in Cot-mediated MAPK activation has not been identified. The serine/threonine kinase Cot (also known as Tpl2) is a member of the MAP kinase kinase kinase (MAP3K) family that is known to regulate oncogenic and inflammatory pathways; however, the mechanism(s) of its regulation are not precisely known. In this report, we identify an 830-amino acid novel human KSR, designated hKSR-2, using predictions from genomic data base mining based on the structural profile of the KSR kinase domain. We show that, similar to the known human KSR, hKSR-2 co-immunoprecipitates with many signaling components of the Ras/MAPK pathway, including Ras, Raf, MEK-1, and ERK-1/2. In addition, we demonstrate that hKSR-2 co-immunoprecipitates with Cot and that co-expression of hKSR-2 with Cot significantly reduces Cot-mediated MAPK and NF-κB activation. This inhibition is specific to Cot, because Ras-induced ERK and IκB kinase-induced NF-κB activation are not significantly affected by hKSR-2 co-expression. Moreover, Cot-induced interleukin-8 production in HeLa cells is almost completely inhibited by the concurrent expression of hKSR-2, whereas transforming growth factor β-activated kinase 1 (TAK1)/TAK1-binding protein 1 (TAB1)-induced interleukin-8 production is not affected by hKSR-2 co-expression. Taken together, these results indicate that hKSR-2, a new member of the KSR family, negatively regulates Cot-mediated MAP kinase and NF-κB pathway signaling. Kinase suppressor of Ras (KSR) is an integral and conserved component of the Ras signaling pathway. Although KSR is a positive regulator of the Ras/mitogen-activated protein (MAP) kinase pathway, the role of KSR in Cot-mediated MAPK activation has not been identified. The serine/threonine kinase Cot (also known as Tpl2) is a member of the MAP kinase kinase kinase (MAP3K) family that is known to regulate oncogenic and inflammatory pathways; however, the mechanism(s) of its regulation are not precisely known. In this report, we identify an 830-amino acid novel human KSR, designated hKSR-2, using predictions from genomic data base mining based on the structural profile of the KSR kinase domain. We show that, similar to the known human KSR, hKSR-2 co-immunoprecipitates with many signaling components of the Ras/MAPK pathway, including Ras, Raf, MEK-1, and ERK-1/2. In addition, we demonstrate that hKSR-2 co-immunoprecipitates with Cot and that co-expression of hKSR-2 with Cot significantly reduces Cot-mediated MAPK and NF-κB activation. This inhibition is specific to Cot, because Ras-induced ERK and IκB kinase-induced NF-κB activation are not significantly affected by hKSR-2 co-expression. Moreover, Cot-induced interleukin-8 production in HeLa cells is almost completely inhibited by the concurrent expression of hKSR-2, whereas transforming growth factor β-activated kinase 1 (TAK1)/TAK1-binding protein 1 (TAB1)-induced interleukin-8 production is not affected by hKSR-2 co-expression. Taken together, these results indicate that hKSR-2, a new member of the KSR family, negatively regulates Cot-mediated MAP kinase and NF-κB pathway signaling. KSR 1The abbreviations used are: KSRkinase suppressor of RashKSR-2human kinase suppressor of Ras-2MAPmitogen-activated proteinMAPKMAP kinaseMAP3KMAPK kinase kinaseaaamino acid(s)ERKextracellular signal-regulated kinaseMEKMAPK/ERK kinaseDMEMDulbecco's modified Eagle's mediumELISAenzyme-linked immunosorbent assayHEKhuman embryonic kidneyIKKIκB kinaseIL-8interleukin 8LPSlipopolysaccharideMOPS4-morpholinepropanesulfonic acidTAK1transforming growth factor β-activated kinase 1TAB1TAK-1-binding protein 1TNF-αtumor necrosis factor-α. constitutes a protein kinase family that is structurally related to the Raf family of kinases (1Sundaram M. Han M. Cell. 1995; 83: 889-901Abstract Full Text PDF PubMed Scopus (258) Google Scholar). However, there are significant functional differences between the KSR and Raf protein families. KSR was initially isolated by selection and complementation of genetic mutations in Drosophila and Caenorhabditis elegans (1Sundaram M. Han M. Cell. 1995; 83: 889-901Abstract Full Text PDF PubMed Scopus (258) Google Scholar, 2Kornfeld K. Hom D.B. Horvitz H.R. Cell. 1995; 83: 903-913Abstract Full Text PDF PubMed Scopus (250) Google Scholar, 3Therrien M. Chang H.C. Solomon N.M. Karim F.D. Wassarman D.A. Rubin G.M. Cell. 1995; 83: 879-888Abstract Full Text PDF PubMed Scopus (340) Google Scholar). These studies determined that KSR functions downstream of Ras and either upstream of or parallel to Raf kinase. Unlike Raf, KSR does not contain a consensus Ras binding domain (RBD) (3Therrien M. Chang H.C. Solomon N.M. Karim F.D. Wassarman D.A. Rubin G.M. Cell. 1995; 83: 879-888Abstract Full Text PDF PubMed Scopus (340) Google Scholar, 4Michaud N.R. Therrien M. Cacace A. Edsall L.C. Spiegel S. Rubin G.M. Morrison D.K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12792-12796Crossref PubMed Scopus (145) Google Scholar, 5Zhou M. Horita D.A. Waugh D.S. Byrd R.A. Morrison D.K. J. Mol. Biol. 2002; 315: 435-446Crossref PubMed Scopus (70) Google Scholar). The amino-terminal regions of Drosophila and mammalian KSR contain four conserved domains, i.e. CA1 to CA4. CA1 is a domain unique to KSR, proline-rich CA2 contains a Src homology 2 (SH2) domain, CA3 is a cysteine-rich domain, and CA4 is serine/threonine-rich domain (3Therrien M. Chang H.C. Solomon N.M. Karim F.D. Wassarman D.A. Rubin G.M. Cell. 1995; 83: 879-888Abstract Full Text PDF PubMed Scopus (340) Google Scholar). The carboxyl-terminal region of KSR contains the CA5 domain, which encompasses the 11 conserved kinase subdomains found in all known protein kinases. kinase suppressor of Ras human kinase suppressor of Ras-2 mitogen-activated protein MAP kinase MAPK kinase kinase amino acid(s) extracellular signal-regulated kinase MAPK/ERK kinase Dulbecco's modified Eagle's medium enzyme-linked immunosorbent assay human embryonic kidney IκB kinase interleukin 8 lipopolysaccharide 4-morpholinepropanesulfonic acid transforming growth factor β-activated kinase 1 TAK-1-binding protein 1 tumor necrosis factor-α. Studies using KSR knock-out mice and RNA interference (RNAi) technology have confirmed a positive regulatory role of KSR in Ras-mediated MAP kinase activation (2Kornfeld K. Hom D.B. Horvitz H.R. Cell. 1995; 83: 903-913Abstract Full Text PDF PubMed Scopus (250) Google Scholar, 6Nguyen A. Burack W.R. Stock J.L. Kortum R. Chaika O.V. Afkarian M. Muller W.J. Murphy K.M. Morrison D.K. Lewis R.E. McNeish J. Shaw A.S. Mol. Cell. Biol. 2002; 22: 3035-3045Crossref PubMed Scopus (229) Google Scholar). Given that KSR lacks several key properties of a protein kinase, including a conserved lysine in its kinase subdomain II, the role of its kinase activity is still unsettled. KSR may exert its effect through direct phosphorylation of Raf-1 (7Xing H.R. Kolesnick R. J. Biol. Chem. 2001; 276: 9733-9741Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 8Zhang Y. Yao B. Delikat S. Bayoumy S. Lin X.H. Basu S. McGinley M. Chan-Hui P.Y. Lichenstein H. Kolesnick R. Cell. 1997; 89: 63-72Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 9Yan F. Polk D.B. Cancer Res. 2001; 61: 963-969PubMed Google Scholar) and may also function as a scaffolding protein through its interactions with multiple components of the Ras/MAP kinase pathway such as Raf-1, MEK1/2, and ERK1/2 (10Stewart S. Sundaram M. Zhang Y. Lee J. Han M. Guan K.L. Mol. Cell. Biol. 1999; 19: 5523-5534Crossref PubMed Scopus (181) Google Scholar). Thus, it has been proposed that KSR may function as a scaffolding protein or a kinase for the coordination of the Ras/MAP kinase pathway (11Roy F. Laberge G. Douziech M. Ferland-McCollough D. Therrien M. Genes Dev. 2002; 16: 427-438Crossref PubMed Scopus (173) Google Scholar, 12Roy F. Therrien M. Curr. Biol. 2002; 12: R325-R327Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 13Peyssonnaux C. Eychene A. Biol. Cell. 2001; 93: 53-62Crossref PubMed Scopus (619) Google Scholar). Cot (Tpl2 in rat), a human proto-oncogene (14Sasai H. Higashi T. Nakamori S. Miyoshi J. Suzuki F. Nomura T. Kakunaga T. Br. J. Cancer. 1993; 67: 262-267Crossref PubMed Scopus (7) Google Scholar, 15Miyoshi J. Higashi T. Mukai H. Ohuchi T. Kakunaga T. Mol. Cell. Biol. 1991; 11: 4088-4096Crossref PubMed Scopus (106) Google Scholar), is a serine/threonine kinase in the MAP kinase kinase kinase (MAP3K) family (MAP3K8) (16Schlesinger T.K. Fanger G.R. Yujiri T. Johnson G.L. Front. Biosci. 1998; 3: D1181-D1186Crossref PubMed Google Scholar). Cot expression has been shown to induce ERK and JNK activation (17Dumitru C.D. Ceci J.D. Tsatsanis C. Kontoyiannis D. Stamatakis K. Lin J.H. Patriotis C. Jenkins N.A. Copeland N.G. Kollias G. Tsichlis P.N. Cell. 2000; 103: 1071-1083Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, 18Chiariello M. Marinissen M.J. Gutkind J.S. Mol. Cell. Biol. 2000; 20: 1747-1758Crossref PubMed Scopus (168) Google Scholar). Similar to Raf, Cot is a MEK-1 kinase upstream of ERK pathway. Overexpression of Cot in CD3-activated T cells leads to IL-2 production, suggesting that Cot may play a role in T cell activation (19Ballester A. Tobena R. Lisbona C. Calvo V. Alemany S. J. Immunol. 1997; 159: 1613-1618PubMed Google Scholar, 20Gilks C.B. Bear S.E. Grimes H.L. Tsichlis P.N. Mol. Cell. Biol. 1993; 13: 1759-1768Crossref PubMed Scopus (201) Google Scholar). In addition, Cot has been shown to activate members of the NF-κB family, possibly by activating the IκB kinase (IKK) complex through the NF-κB-inducing kinase (NIK) or by inducing the degradation of the inhibitory protein p105 (21Kane L.P. Mollenauer M.N. Xu Z. Turck C.W. Weiss A. Mol. Cell. Biol. 2002; 22: 5962-5974Crossref PubMed Scopus (136) Google Scholar, 22O'Mahony A. Lin X. Geleziunas R. Greene W.C. Mol. Cell. Biol. 2000; 20: 1170-1178Crossref PubMed Scopus (102) Google Scholar, 23Salmeron A. Janzen J. Soneji Y. Bump N. Kamens J. Allen H. Ley S.C. J. Biol. Chem. 2001; 276: 22215-22222Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). Recent studies using Cot knock-out mice point to a pivotal role of Cot in the LPS-induced production of TNF-α and (17Dumitru C.D. Ceci J.D. Tsatsanis C. Kontoyiannis D. Stamatakis K. Lin J.H. Patriotis C. Jenkins N.A. Copeland N.G. Kollias G. Tsichlis P.N. Cell. 2000; 103: 1071-1083Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, C.D. J. Tsichlis P.N. J. 2002; PubMed Scopus Google Scholar). these the of Cot regulation Given that activation of Cot and Raf to activation of downstream MAP kinase pathway components and that KSR is known to function as a regulatory protein in the kinase pathway, we have the functional of Cot and a data base mining with a conserved kinase domain we have and a novel KSR family Similar to C. elegans this to the CA1 domain of the KSR family and has and amino acid with the known human hKSR-2 with Cot in and hKSR-2 expression Cot-mediated ERK and NF-κB activation. the co-expression of hKSR-2 Cot-mediated production in HeLa These data a novel inhibitory role for hKSR-2 in Cot-mediated and the hKSR-2 and by using the human hKSR-2 was by The was in to the and the was the of is The domain of KSR was by a the lysine and the the The confirmed by and and cell in with and as to growth for all and kinase cells either with the or the domain of hKSR-2 of mammalian HeLa and cells with and with either of in a or with in a hKSR-2 the hKSR-2 from to in a the Cot 2 HeLa cells a of to the cell medium was from with to with and either or with human TNF-α for the cells from with to The with used and for and and on for in a 1 1 1 1 and by for determined using the protein assay protein with 1 of was to with a and by on the in and the using a with as Cot and of was to of and of to of the for 2 The in and in and was as by and to using in and with Cot and using to using an Cot Kinase kinase was from cell using to The in kinase and with of and in kinase and and the kinase was by the of and and by and the using the In Kinase of cell with the the with The hKSR-2 was for with Cot in a and isolated on or Raf in the of of and The and as and on a using as for in 1 from the assay with NF-κB and a to the of cell was to a for a The was to a by a of of HeLa cells and in these determined using the from This assay is specific for with a of in and in an determined by to a with a and the factor was of hKSR-2 was from genomic data base mining using the structural of the of kinases. all of the of serine/threonine and kinases from the data base using the The structural in the of multiple which used to the predictions using the which was to the known human KSR, was identified. This was by an The region was as a for and and from a human The of an upstream of the that this contains the on the multiple of all known KSR family the amino of the and of by to the hKSR-2 which has a that an protein kinase. hKSR-2 contains proline-rich cysteine-rich the serine/threonine the consensus MAPK phosphorylation of and the conserved kinase domain CA5 However, hKSR-2 lacks subdomain which is similar to the known and is a domain that is unique to the KSR family (3Therrien M. Chang H.C. Solomon N.M. Karim F.D. Wassarman D.A. Rubin G.M. Cell. 1995; 83: 879-888Abstract Full Text PDF PubMed Scopus (340) Google Scholar). of hKSR-2 was using and a was from a kidney The has to hKSR-2 and the protein has the amino acid with that hKSR-2 is in and kidney not of hKSR-2 with the of MAPK hKSR-2 with components of the MAP kinase pathway, we using of Similar to the known KSR, hKSR-2 also with Raf, and ERK D.K. J. Sci. 2001; PubMed Google Scholar). using not of these Cot is an signaling kinase upstream of MEK-1 and has been shown to a of ERK in we to the of hKSR-2 with 2 that Cot with hKSR-2 the are in Cot and hKSR-2 in of with the or the and the of the of hKSR-2 and Cot, we with hKSR-2 and family is known to an complex with K. T. S. Y. Suzuki M. N. J. M. K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). is in However, hKSR-2 is not in the complex suggesting that hKSR-2 with Cot and not with by with confirmed the of hKSR-2 in these The between hKSR-2 and Cot is either the hKSR-2 or the domain of hKSR-2 is a of Cot not effect its with hKSR-2, as we Cot and hKSR-2 in this not These data that the of hKSR-2 is for this the region of Cot is not for its with hKSR-2 Cot-induced ERK in a the of the of hKSR-2 and Cot in the downstream MAP kinase signaling pathway, we cell in which hKSR-2 and Cot with to ERK1/2 and ERK1/2 and of Cot ERK as with ERK1/2 of hKSR-2 reduces Cot ERK activation by by The expression of Cot, and hKSR-2 with the and similar of expression of these and The ERK activation is not significantly by by the co-expression of hKSR-2 which that hKSR-2 Cot-mediated ERK activation. has been to have a positive and a regulator of based on its expression N.R. Therrien M. K. Copeland T. Rubin G.M. Morrison D.K. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). the that the inhibitory effect on Cot by hKSR-2 is not to its we have hKSR-2 Cot We found a in the of Cot-induced ERK activation by expression in a The expression of Cot, and hKSR-2 with the and similar of expression of these and The ERK in based on the ERK in and with to the Cot We that the hKSR-2 inhibition of Cot is not an of hKSR-2 Cot-induced NF-κB activity regulates NF-κB activation by the complex through the NF-κB-inducing kinase, which is an X. Y. Geleziunas R. Greene W.C. 1999; Full Text Full Text PDF PubMed Google Scholar) or through a that the of the NF-κB inhibitory protein p105 (21Kane L.P. Mollenauer M.N. Xu Z. Turck C.W. Weiss A. Mol. Cell. Biol. 2002; 22: 5962-5974Crossref PubMed Scopus (136) Google Scholar, X. Y. Geleziunas R. Greene W.C. 1999; Full Text Full Text PDF PubMed Google Scholar, A. Ley S.C. 1999; PubMed Scopus Google Scholar). In addition, Cot with and the degradation of p105 and family members A. Ley S.C. 1999; PubMed Scopus Google Scholar). by NF-κB Cot a significant role in the of hKSR-2 expression has an effect on the Cot-induced NF-κB we used a assay to NF-κB activation. shown in of a in expression of the with of hKSR-2 not activate NF-κB in this However, Cot-induced NF-κB activation is inhibited by the co-expression of hKSR-2 by The expression of in the by Similar to ERK in a hKSR-2 Cot-mediated NF-κB in suggesting that hKSR-2 inhibition of Cot is not an of hKSR-2 NF-κB the inhibition of Cot-induced NF-κB activation by hKSR-2 is through Cot or through signaling components of the pathway. this we and hKSR-2 and determined the effect of hKSR-2 on NF-κB activation. In to with Cot, co-expression of hKSR-2 not have effect on the NF-κB activation These results demonstrate the of the Cot inhibition by hKSR-2 and show that the inhibition is not through hKSR-2 Kinase of Cot in an in Kinase that the kinase activity of Cot is for the activation of ERK and we in kinase to hKSR-2 is Cot kinase We the Cot in the or of hKSR-2 using a as a hKSR-2 Cot activity by a of hKSR-2 whereas phosphorylation was by a of hKSR-2 This that hKSR-2 Cot-mediated not phosphorylation in this The of phosphorylation by either Cot or Raf-1 was the of hKSR-2 shown the of hKSR-2 Cot-mediated in HeLa kinase activity is upstream of and JNK activation and is for the production of LPS-induced inflammatory such as TNF-α and (17Dumitru C.D. Ceci J.D. Tsatsanis C. Kontoyiannis D. Stamatakis K. Lin J.H. Patriotis C. Jenkins N.A. Copeland N.G. Kollias G. Tsichlis P.N. Cell. 2000; 103: 1071-1083Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, C.D. J. Tsichlis P.N. J. 2002; PubMed Scopus Google Scholar). a and a has been shown to in by ERK pathway signaling C. S. G. 1999; 67: PubMed Google we the that Cot kinase activity also regulates was a significant in production the of Cot in the HeLa cell This Cot-induced production was by the co-expression of hKSR-2 Similar to T. Xu H. B. Han J. H. Murphy J.D. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, H. J. S. A. A. M. R. A. J. K. K. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), of in this also However, co-expression of hKSR-2 with not a in the of Thus, the of hKSR-2 to Cot-induced production in HeLa cells is as hKSR-2 effect on These results show a inhibitory role of hKSR-2 in Cot-induced KSR was as a positive regulator of the kinase signaling pathway in Drosophila and C. elegans A. C. D. G. J. Eychene A. Curr. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). have that KSR may its function either as a protein through with signaling including Ras, Raf, and (10Stewart S. Sundaram M. Zhang Y. Lee J. Han M. Guan K.L. Mol. Cell. Biol. 1999; 19: 5523-5534Crossref PubMed Scopus (181) Google Scholar, M. N.R. Rubin G.M. Morrison D.K. Genes Dev. PubMed Scopus Google Scholar, H. K. Curr. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) or through direct phosphorylation of Raf (7Xing H.R. Kolesnick R. J. Biol. Chem. 2001; 276: 9733-9741Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 8Zhang Y. Yao B. Delikat S. Bayoumy S. Lin X.H. Basu S. McGinley M. Chan-Hui P.Y. Lichenstein H. Kolesnick R. Cell. 1997; 89: 63-72Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 9Yan F. Polk D.B. Cancer Res. 2001; 61: 963-969PubMed Google Scholar). In the we a novel member of KSR family, hKSR-2, which was by genomic data base mining using structural of of serine/threonine and kinases. human was used to hKSR-2, and it has the and the with the known human Similar to the of the known KSR, we have that hKSR-2 is an integral component of the MAP kinase pathway through its with the members of MAP kinase pathway, including Raf, and We have also a of hKSR-2 with Cot, a member of This between hKSR-2 and Cot is either the hKSR-2 or the domain of hKSR-2 is This that the of hKSR-2 is for this we have that the domain the region of Cot is to with the of Cot was in a for transforming from a human cell J. Higashi T. Mukai H. Ohuchi T. Kakunaga T. Mol. Cell. Biol. 1991; 11: 4088-4096Crossref PubMed Scopus (106) Google Scholar). Although the of Cot regulation is not a by that kinase Cot activity by the phosphorylation of the (21Kane L.P. Mollenauer M.N. Xu Z. Turck C.W. Weiss A. Mol. Cell. Biol. 2002; 22: 5962-5974Crossref PubMed Scopus (136) Google Scholar). In this we for a regulatory of Cot by In an in kinase hKSR-2 the activity of Cot an MEK-1 is used as a Cot kinase activity is upstream of and JNK activation M. Marinissen M.J. Gutkind J.S. Mol. Cell. Biol. 2000; 20: 1747-1758Crossref PubMed Scopus (168) Google Scholar, Lisbona C. R. A. Calvo V. Alemany S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Z. T. Y. C. 2001; PubMed Scopus Google Scholar). in several cell Cot activity regulates NF-κB activation by the complex through the NF-κB-inducing kinase, which is an X. Y. Geleziunas R. Greene W.C. 1999; Full Text Full Text PDF PubMed Google Scholar) or through a that the of the NF-κB inhibitory protein p105 (21Kane L.P. Mollenauer M.N. Xu Z. Turck C.W. Weiss A. Mol. Cell. Biol. 2002; 22: 5962-5974Crossref PubMed Scopus (136) Google Scholar, 23Salmeron A. Janzen J. Soneji Y. Bump N. Kamens J. Allen H. Ley S.C. J. Biol. Chem. 2001; 276: 22215-22222Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, A. Ley S.C. 1999; PubMed Scopus Google Scholar). We demonstrate that Cot-induced NF-κB activity is significantly inhibited by the co-expression of This inhibition of NF-κB by hKSR-2 is specific for Cot-induced NF-κB activation and is of or upstream of because NF-κB is not affected by the co-expression of hKSR-2 inhibited the Cot-mediated activation of by In hKSR-2 the activation by to These data indicate that hKSR-2 Cot kinase activity downstream signaling in the MAP kinase and NF-κB on the Cot knock-out data (17Dumitru C.D. Ceci J.D. Tsatsanis C. Kontoyiannis D. Stamatakis K. Lin J.H. Patriotis C. Jenkins N.A. Copeland N.G. Kollias G. Tsichlis P.N. Cell. 2000; 103: 1071-1083Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar), it is that Cot kinase activity is for the production of LPS-induced production of inflammatory such as TNF-α and and inflammatory such as by R. M. Alemany S. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). We that Cot activity may also for production of the of Cot in HeLa cells an production of and this the kinase activity of Cot, because the of a Cot does not have an effect on with the inhibition of MAP kinase and Cot-induced production by a is a and a that is by many cell including and cells in to inflammatory is in the of many inflammatory including and N. J. 1998; PubMed Scopus Google Scholar) and has been in the of these inflammatory that Cot production, through MAP kinase and NF-κB data and the results of that that is by MAP kinase pathway signaling C. S. G. 1999; 67: PubMed Google Scholar, A. S. S. S. Basu J. M. J. 2002; PubMed Scopus Google Scholar, M. J. M. D. Cell. 2001; 3: PubMed Scopus Google Scholar, A. J. Res. 2001; PubMed Scopus Google Scholar, R. M. Johnson K. K. N. R. 2000; PubMed Scopus Google Scholar). member of family, is also shown to induce production by activating the NF-κB pathway with its H. J. S. A. A. M. R. A. J. K. K. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). Although we this data in we also that hKSR-2 does not have effect on production with this we not to between these in The of of Cot not of the that the of hKSR-2 and Cot is a The in regulation of the Raf, and by hKSR-2 is the of Cot in HeLa cells not to an of such as and not These are with the of the Cot knock-out in which Cot LPS-induced TNF-α and production in and (17Dumitru C.D. Ceci J.D. Tsatsanis C. Kontoyiannis D. Stamatakis K. Lin J.H. Patriotis C. Jenkins N.A. Copeland N.G. Kollias G. Tsichlis P.N. Cell. 2000; 103: 1071-1083Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar). are to the effect of Cot on production and its role in Although data are with a in which the effect of hKSR-2 is specific to Cot, the of this regulation is Given that Cot and KSR are known to with and that the of hKSR-2 with is in cells of inhibition of Cot may the of a Cot binding on However, the that KSR does not ERK activation through the that KSR is binding to and a Cot phosphorylation on Thus, a of hKSR-2 inhibition of Cot is that hKSR-2 to Cot to its activation of In we have and isolated a novel human KSR hKSR-2, and data indicate that hKSR-2 functions as a regulator for Cot-mediated signaling. We also that Cot production, possibly through the ERK and NF-κB signaling and that Cot-induced production is inhibited by co-expression of These with the positive regulatory role of KSR in the pathway. this is the suggesting that a KSR family member may function as a positive or a regulatory on its We for hKSR-2 through the kinase We also the members of for and on the to and for

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