IRAK2 counterbalances oncogenic Smurf1 in colon cancer cells by dictating ER stress

Cellular Signalling
Jingwen LiuGuanglong Dong

Abstract

The endoplasmic reticulum (ER) is a cellular organelle with central roles in maintaining proteostasis. The accumulation of misfolded proteins in the ER lumen causes ER stress. Cells evoke an evolutionarily conserved adaptive signaling network "unfolded protein response" to restore ER homeostasis, however, how the signaling network is delicately orchestrated remains largely unrevealed. Meanwhile, the HECT type E3 ligase Smad ubiquitylation regulatory factor 1 (Smurf1) has been reported to play critical roles in several important biological pathways by targeting distinct substrates for ubiquitylation, including WFS1, a critical mediator of ER stress, whereas the regulation of Smurf1 activity and abundance upon ER stress are poorly understood. Here, we identified Interleukin-1 Receptor Associated Kinase 2 (IRAK2) as a novel modulator of Smurf1 in response to ER stress induced cell death. Mechanistically, IRAK2 phosphorylates Smurf1 at threonine residues to promote its self-degradation by ubiquitylation, resulting in altered cascade of ER effectors to induce apoptosis. Reduced IRAK2 expression correlates with increased Smurf1 abundance in human colorectal cancer cells. Taken together, these findings demonstrate a novel mechanism of...Continue Reading

Citations

Jan 16, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Yi LiuZe Li
Nov 19, 2020·Cancer Gene Therapy·Qin XiaLei Dong
Mar 16, 2021·Frontiers in Oncology·Longtao YangHui Lin
Nov 8, 2021·Current Opinion in Hematology·Joshua Bennett, Daniel T Starczynowski

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