Opposing regulation of endoplasmic reticulum retention under stress by ERp44 and PDIA6.

Conditions of endoplasmic reticulum (ER) stress reduce protein synthesis by provoking translation regulation, governed by the eIF2α kinase PERK. When PERK is inhibited during ER stress, retention of a selective subset of glycoproteins occurs, a phenomenon we termed selective ER retention (sERr). sERr clients are enriched with tyrosine kinase receptors (RTKs), which form large molecular weight disulfide bonded complexes in the ER.

Phosphorylation of GCN2 by mTOR confers adaptation to conditions of hyper-mTOR activation under stress.

Adaptation to the shortage in free amino acids (AA) is mediated by 2 pathways, the integrated stress response (ISR) and the mechanistic target of rapamycin (mTOR). In response to reduced levels, primarily of leucine or arginine, mTOR in its complex 1 configuration (mTORC1) is suppressed leading to a decrease in translation initiation and elongation. The eIF2α kinase general control nonderepressible 2 (GCN2) is activated by uncharged tRNAs, leading to induction of the ISR in response to a broader range of AA shortage.

An mTORC1 to HRI signaling axis promotes cytotoxicity of proteasome inhibitors in multiple myeloma.

Multiple myeloma (MM) causes approximately 20% of deaths from blood cancers. Notwithstanding significant therapeutic progress, such as with proteasome inhibitors (PIs), MM remains incurable due to the development of resistance. mTORC1 is a key metabolic regulator, which frequently becomes dysregulated in cancer.

Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells.

The endoplasmic reticulum (ER) is a dynamic organelle that responds to demand in secretory proteins by undergoing expansion. The mechanisms that control the homeostasis of ER size and function involve the activation of the unfolded protein response (UPR). The UPR plays a role in various effector functions of immune cells.

Aripiprazole Cytotoxicity Coincides with Activation of the Unfolded Protein Response in Human Hepatic Cells.

Schizophrenia is a mental disease that results in decreased life expectancy and well-being by promoting obesity and sedentary lifestyles. Schizophrenia is treated by antipsychotic drugs. Although the second-generation antipsychotics (SGA), Olanzapine and Aripiprazole, are more effective in treating schizophrenia, they display a higher risk of metabolic side effects, mostly by development of diabetes and insulin resistance, weight gain, and dyslipidemia.

Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy.

The integrated stress response (ISR) converges on eIF2α phosphorylation to regulate protein synthesis. ISR is activated by several stress conditions, including endoplasmic reticulum (ER) stress, executed by protein kinase R-like endoplasmic reticulum kinase (PERK). We report that ER stress combined with ISR inhibition causes an impaired maturation of several tyrosine kinase receptors (RTKs), consistent with a partial block of their trafficking from the ER to the Golgi.

The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors.

IRE1, PERK, and ATF6 are the three transducers of the mammalian canonical unfolded protein response (UPR). GSK2606414 is a potent inhibitor of PERK, while KIRA6 inhibits the kinase activity of IRE1. Both molecules are frequently used to probe the biological roles of the UPR in mammalian cells.