|My research concerns the identification and mapping of signaling pathways involved in inflammation. Currently, we are investigating the mechanism of activation of TAK1, a mitogen activated protein kinase kinase kinase (MAPKKK). TAK1 is activated by pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor-? (TNF-?), and also by bacterial lipopolysaccharides (LPS). Engagement of these three stimuli with their receptors leads to the activation of the inflammatory response via the JNK, p38? and NF?B pathways which all lie downstream of TAK1. However, dysregulation of these pathways can lead to chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and asthma. As TAK1 is a key component in transducing inflammatory signals, inhibition of TAK1 by therapeutic means may be attractive as treatment for these diseases.
In vivo, TAK1 exists as two distinct heterotrimeric forms. One consists of TAK1-TAB1-TAB2 and the other TAK1-TAB1-TAB3. It is known that TAB1 is required for TAK1 activity, and that TAB2 or TAB3 may act as a link with upstream regulators. My recent work has shown that p38? is involved in the down-regulation of TAK1 activity and the identification of TAB3 as a new binding partner of TAK1.
- Sutejo R, Yeo DS, Myaing MZ, Hui C, Xia J, Ko D, Cheung PCF, Tan BH and Sugrue RJ. (2013). Activation of Type I and III Interferon Signalling Pathways Occurs in Lung Epithelial Cells Infected with Low Pathogenic Avian Influenza Viruses.. PLoS ONE, 7(3), e33732.
- Dai L, Thu CA, Liu X, Xi J and Cheung PCF. (2012). TAK1, more than just innate immunity. IUBMB Life, 64(10), 825-834.
- Enesa K, Ordureau A, Smith H, Barford D, Cheung PCF, Patterson-Kane J, Arthur JS, Cohen P. (2012). Defective production of type 1 interferons in mice expressing an E3-ligase deficient mutant of Pellino1. Journal of Biological Chemistry, 287(41), 34825-35.
- Goh ET, Arthur JS, Cheung PCF, Akira S, Toth R, Cohen P. (2012). Identification of the protein kinases that activate the E3 ubiquitin ligase Pellino 1 in the innate immune system.. Biochemical Journal, 441(1), 339-346.
- Lam CRI, Tan MJ, Tan SH, Tang MBY, Cheung PCF and Tan NS. (2011). TAK1 regulates SCF expression to modulate PKB activity that protects keratinocytes from ROS-induced apoptosis.. Journal of Biological Chemistry, 18(7), 1120-1129.