sMEK1 promotes crosstalk between IRE1 and Akt signalling pathways: Evidence for a novel IRE1/sMEK1/Akt complex

The Unfolded Protein Response (UPR) is a dynamic cellular pathway that helps maintain proteostasis during endoplasmic reticulum (ER) stress. One of the key UPR sensors is IRE1, which plays a central role in managing ER stress and interacts with other cellular pathways to regulate cell homeostasis. The Akt signalling pathway, on the other hand, is a crucial survival pathway involved in diverse cellular functions like growth, proliferation, glucose metabolism, and survival. This study explores the interplay between these two important cell signalling pathways. Specifically, our study revealed that IRE1 negatively regulates Akt through the protein phosphatase sMEK1. We identified sMEK1 and Akt as novel interacting partners of IRE1, which together form a ternary complex that helps coordinate the IRE1 and Akt signalling networks. The IRE1/sMEK1/Akt ternary complex results in the dephosphorylation of Akt by sMEK1 in the presence of activated IRE1. Together, this study sheds light on the molecular mechanism underlying the UPR/Akt link and provides valuable insights into the overall impact of their interaction.