2023年9月8日 · Oncogenic KRAS promoted IRE1α protein stability through extracellular signal-regulated kinase (ERK)-dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase.

2023年9月27日 · Writing in Science, Lv et al. report that oncogenic KRAS ensures protein quality control in cancer cells by stabilizing the major mediator of the unfolded protein response (UPR), IRE1α. Cells...

2023年1月9日 · IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA...

2024年4月1日 · In this review, we deliver evolutive and structural insights on IRE1 and further describe how this protein interaction network (interactome) regulates IRE1 signaling abilities or mediates other cellular processes through catalytic-independent mechanisms.

KRAS activation diminishes ER stress in KRAS-mutant cells, predominantly via the oncogenic kinase-mediated phosphorylation of IRE1a (Figure 1A). Upon KRAS suppression, a disruption in proteostasis emerges, evident through pro-nounced protein aggregation observed in doxycycline inducible KRAS G12D and KRAS G12C models (Figure 1B).

Lv et al. discovered a mechanism that rewires the proteostasis network to escape oncogenic KRAS addiction and promote resistance to KRAS inhibitors (KRASi). Inactivation of mutant KRAS, a key oncogenic driver for many human cancers, shuts down major proteostasis regulatory pathways, causing severe protein aggregations.

RTK-mediated reactivation of ERK and hyperacti-vation of AKT sustained the unconventional phosphorylation of IRE1 in the KRASi-resistant. tumors, which consequently restored its protein stability and reestablished proteostasis. Gen-etic or pharmacological suppression of IRE1. – activated protein kinase) inhibitors.

2023年2月1日 · 使用 NSCLC 的KRAS 小鼠模型，发现 癌细胞固有的 IRE1α 促进显着的肿瘤内免疫抑制，从而促进恶性进展。 首先，研究人员开发了一个计算模型，量化剪接的XBP1 mRNA 亚型 (XBP1s) 相对于TCGA 数据库中RNA-seq 数据的总XBP1转录本的百分比，以确定 IRE1α-XBP1 信号在 NSCLC 患者中的临床相关性。 与高XBP1相比，低XBP1患者的总生存期 (OS) 显着改善，XBP1高中位数为 37.6 个月，XBP1低中位数为 58.3 个月。

2023年9月9日 · 该研究首次报道了蛋白质稳态调控网络重编程的分子机制及其在kras抑制剂耐药性中的重要功能。

2023年11月13日 · In the remaining cells, a subset can reactivate one of the endoplasmic reticulum (ER) stress sensors, specifically the inositol-requiring enzyme 1 alpha (IRE1α) branch of the unfolded protein response (UPR). This adaptation enables the cells to overcome their reliance on oncogenic KRAS, enhancing their resistance to KRASi (Figure 1).