Protein kinase ASK1

Protein kinase ASK1, a member of the mitogen-activated protein kinase kinase kinase family, activates JNK and p38 MAP kinase signaling pathways in response to various stress stimuli, including oxidative stress, endoplasmic reticulum stress, and calcium ion influx . ASK1 plays a key role in the pathogenesis of multiple diseases including cancer, neurodegeneration and cardiovascular diseases and is considered as a promising therapeutic target. The activity of ASK1 is regulated by several other proteins including thioredoxin and the 14-3-3 protein that both function as physiological inhibitors of ASK1. Main goal of this project is to elucidtae the inhibitory mechanism of ASK1 through interaction with regulatory proteins 14-3-3 and thioredoxin (TRX1). This project was funded by Czech Science Foundation (Project 14-10061S). 

The activation mechanism of ASK1 in response to oxidative stress. ASK1 forms homo-oligomer thorough the C-terminal coiled-coil domain. In steady state, Trx and 14-3-3 proteins bind to ASK1 and negatively regulate the activation of ASK1. In response to oxidative stress, Trx and 14-3-3 proteins dissociate from ASK1 while TRAF2 and TRAF6 are recruited to ASK1 and bind to ASK1, resulting in homophilic interaction of ASK1 through the N-terminal coiled-coil domain and activation of ASK1. Adapted from Shiizaki et al. Advances in Biological Regulation (2012)