hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kappaB pathways in inflammation.
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.
Channavajhala
Padma L
PL
Department of Inflammation, Wyeth Research, Cambridge, MA 02140, USA.
Rao
Vikram R
VR
Spaulding
Vikki
V
Lin
Lih-Ling
LL
Zhang
Y George
YG
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*
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