HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 47, 47089-47097, November 21, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/47/47089    most recent M306002200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Channavajhala, P. L. Articles by Zhang, Y. Search for Related Content PubMed PubMed Citation Articles by Channavajhala, P. L. Articles by Zhang, Y. Social Bookmarking                      What's this?

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

Padma L. Channavajhala, Leeying Wu¶, John W. Cuozzo, J. Perry Hall, Wei Liu¶, Lih-Ling Lin, and Yuhua Zhang||

From the Departments of Inflammation and ^¶Genomics, Wyeth Research, Cambridge, Massachussetts 02140

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-B activation. This inhibition is specific to Cot, because Ras-induced ERK and IB kinase-induced NF-B 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 -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-B pathway signaling.

Received for publication, June 6, 2003 , and in revised form, August 25, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY345972.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed. E-mail: pchannavajhala{at}wyeth.com. || To whom correspondence may be addressed: Dept. of Inflammation, Wyeth Research, 200 Cambridge Park Dr., Cambridge, MA 02140. Tel.: 617-665-5421; Fax: 617-665-5499; E-mail: yzhang{at}wyeth.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				X. Wang, R. Patel, and G. P. Studzinski hKSR-2, a vitamin D-regulated gene, inhibits apoptosis in arabinocytosine-treated HL60 leukemia cells Mol. Cancer Ther., September 1, 2008; 7(9): 2798 - 2806. [Abstract] [Full Text] [PDF]

				C. E. Rocheleau, K. Cullison, K. Huang, Y. Bernstein, A. C. Spilker, and M. V. Sundaram The Caenorhabditis elegans ekl (Enhancer of ksr-1 Lethality) Genes Include Putative Components of a Germline Small RNA Pathway Genetics, March 1, 2008; 178(3): 1431 - 1443. [Abstract] [Full Text] [PDF]

				J. P. Hall, Y. Kurdi, S. Hsu, J. Cuozzo, J. Liu, J.-B. Telliez, K. J. Seidl, A. Winkler, Y. Hu, N. Green, et al. Pharmacologic Inhibition of Tpl2 Blocks Inflammatory Responses in Primary Human Monocytes, Synoviocytes, and Blood J. Biol. Chem., November 16, 2007; 282(46): 33295 - 33304. [Abstract] [Full Text] [PDF]

				A. M. Fusello, L. Mandik-Nayak, F. Shih, R. E. Lewis, P. M. Allen, and A. S. Shaw The MAPK Scaffold Kinase Suppressor of Ras Is Involved in ERK Activation by Stress and Proinflammatory Cytokines and Induction of Arthritis J. Immunol., November 1, 2006; 177(9): 6152 - 6158. [Abstract] [Full Text] [PDF]

				R. L. Kortum, D. L. Costanzo, J. Haferbier, S. J. Schreiner, G. L. Razidlo, M.-H. Wu, D. J. Volle, T. Mori, H. Sakaue, N. V. Chaika, et al. The Molecular Scaffold Kinase Suppressor of Ras 1 (KSR1) Regulates Adipogenesis Mol. Cell. Biol., September 1, 2005; 25(17): 7592 - 7604. [Abstract] [Full Text] [PDF]

				B. S. Luciano, S. Hsu, P. L. Channavajhala, L.-L. Lin, and J. W. Cuozzo Phosphorylation of Threonine 290 in the Activation Loop of Tpl2/Cot Is Necessary but Not Sufficient for Kinase Activity J. Biol. Chem., December 10, 2004; 279(50): 52117 - 52123. [Abstract] [Full Text] [PDF]