title: hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kappaB pathways in inflammation.
abstract: Kinase suppressor of ras (KSR) and MEKK3 (MAP kinase kinase kinase) are integral members of the MAP kinase pathway. We have recently identified a new isoform of the KSR family named human kinase suppressor of ras-2 (hKSR-2), and demonstrated that hKSR-2 negatively regulates Cot, a MAP3K family member which is important in inflammation and oncogenesis [P.L. Channavajhala, L. Wu, J.W. Cuozzo, J.P. Hall, W. Liu, L.L. Lin, Y. Zhang, J. Biol. Chem. 278 (2003) 47089-47097]. In this report, we provide evidence that hKSR-2 also regulates the activity of MEKK3 (another MAP3K family member) in HEK-293T cells. We demonstrate that hKSR-2 is a negative regulator of MEKK3-mediated activation of MAP kinase (specifically ERK and JNK) and NF-kappaB pathways, and concurrently inhibits MEKK3-mediated interleukin-8 production. We find that while hKSR-2 blocks MEKK3 activation, it has little to no effect on other members of the MAP3K family, including MEKK4, TAK1, and Ras-Raf, suggesting that its effects are selective.
authors.affiliation: Department of Inflammation, Wyeth Research, Cambridge, MA 02140, USA.
authors.forename: Padma L
authors.initials: PL
authors.lastname: Channavajhala
authors.forename: Vikram R
authors.initials: VR
authors.lastname: Rao
authors.forename: Vikki
authors.initials: V
authors.lastname: Spaulding
authors.forename: Lih-Ling
authors.initials: LL
authors.lastname: Lin
authors.forename: Y George
authors.initials: YG
authors.lastname: Zhang
mesh_terms: D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011994:Recombinant Proteins; C460981:ksr-2 protein, C elegans; D020928:Mitogen-Activated Protein Kinases; D048748:MAP Kinase Kinase Kinase 3; C482625:MAP3K3 protein, human