Regulation of the TAK1 and MEKK3 protein kinases in the inflammatory response.

• Main Author: Cheung, Peter.
• Other Authors: School of Biological Sciences
• Format: Research Report
• Language: English
• Published: 2008
• Subjects: DRNTU::Science::Biological sciences::Biochemistry
• Online Access: http://hdl.handle.net/10356/14227
• Institution: Nanyang Technological University

The present proposal aims to investigate the mechanism of activation of TAKl and MEKK3, two MAP3Ks shown to play key roles in the inflammatory response. Activation of these two protein kinases by the pro-inflammatory cytokines IL-1 and TNFalpha, or by bacterial LPS leads to the expression of pro-inflammatory genes via the NFkappaB, p38alpha and JNK pathways. The IL-1, TNFalpha and LPS signaling pathways are of interest because of their involvement in acute and chronic inflammatory diseases such as septic shock syndrome, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Therefore, inhibition of TAKl and MEKK3 may be beneficial in the treatment of these inflammatory diseases. The regulation of TAKl and MEKK3 is unclear and my aim is to identify regulatory molecules of these two kinases by both a genetic and biochemical approach; the yeast two-hybrid system and tandem affinity purification respectively. Novel proteins identified by these methods will be investigated by both heterologous expression and RNA interference mediated knockdown in human HEK 293, HeLa and Drosophila S2 cells. We have recently identified HSP70 and HSC70 as part of the endogenous TAKl complex and are currently investigating their effects on TAKl regulation.