Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Cancers with activating mutations of KRAS show a high prevalence but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression is post-translationally up-regulated through deubiquitination when the scaffolding function of NDRG3 (N-Myc downstream-regulated gene 3) promotes specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant cancer cells KRAS protein expression, downstream signaling, and cell growth are highly dependent on NDRG3. In conditional Kras knock-in mouse models of pancreatic ductal adenocarcinoma, Ndrg3 depletion abolishes Kras protein expression and suppresses intraepithelial neoplasia formation in pancreas. Mechanistically, KRAS protein binds to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through deubiquitination by USP9X recruited to the complex. This interaction can be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that binds KRAS but is defective in USP9X binding, highly suppressing KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739382 | PMC |
| http://dx.doi.org/10.1038/s41467-024-54476-8 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Integrative profiling of lung cancer biomarkers EGFR, ALK, KRAS, and PD-1 with emphasis on nanomaterials-assisted immunomodulation and targeted therapy.
Front Immunol
September 2025
Department of Thoracic Surgery, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China.
Background: Lung cancer remains the leading cause of cancer-related mortality globally, primarily due to late-stage diagnosis, molecular heterogeneity, and therapy resistance. Key biomarkers such as EGFR, ALK, KRAS, and PD-1 have revolutionized precision oncology; however, comprehensive structural and clinical validation of these targets is crucial to enhance therapeutic efficacy.
Methods: Protein sequences for EGFR, ALK, KRAS, and PD-1 were retrieved from UniProt and modeled using SWISS-MODEL to generate high-confidence 3D structures.
Real-world outcomes of neoadjuvant chemoimmunotherapy in patients with nonsmall cell lung cancer: Predictors of surgery, pathologic complete response, and event-free survival.
Cancer
September 2025
Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York, USA.
Background: Trials of neoadjuvant chemoimmunotherapy (chemoIO) have changed the standard of care for resectable nonsmall cell lung cancer (NSCLC). This study characterizes the outcomes of off-trial patients who received treatment with neoadjuvant chemoIO.
Methods: The authors analyzed records of patients with stage IB-III NSCLC who received neoadjuvant chemoIO with an intent to proceed to surgical resection at three US academic institutions.
Vitamin D Binding Protein, a Ligand of Integrin beta 1, Motivates Both Tumor Cells and Schwann Cells to Promote Perineural Invasion in Pancreatic Ductal Adenocarcinoma.
Adv Sci (Weinh)
September 2025
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, P. R. China.
Perineural invasion (PNI) is a common pathological characteristic of pancreatic ductal adenocarcinoma (PDAC), closely linked to postoperative recurrence, metastasis, and unfavorable prognosis. Nevertheless, the precise mechanisms that govern PNI in PDAC remain poorly elucidated. Here, group-specific component protein (GC) is identified as one of the most significantly upregulated genes related to PNI, primarily derived from malignant ductal cells compared to other cell types.
View Article and Find Full Text PDFDistinct association of HRAS and KRAS with Mn ion illustrated by paramagnetic NMR.
Magn Reson Lett
February 2025
State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China.
Rat sarcoma virus oncogene (RAS) proteins are of crucial oncogenic proteins and are involved in several essential intracellular processes. The RAS protein has an intrinsic metal binding site for Mg, which is important for the conformational stability of the active site. Recently, it was reported that a second metal ion binding site, located further from the active site in HRAS (Harvey RAS homolog), binds Ca with millimolar affinity.
View Article and Find Full Text PDFRadiogenomics-based prediction of and gene mutation in non-small cell lung cancer patients.
Zhong Nan Da Xue Xue Bao Yi Xue Ban
May 2025
Department of Geriatric Pulmonary and Critical Care Medicine, Xiangya Hospital, Central South University; National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha 410008.
Objectives: Non-small cell lung cancer (NSCLC) is associated with poor prognosis, with 30% of patients diagnosed at an advanced stage. Mutations in the and genes are important prognostic factors for NSCLC, and targeted therapies can significantly improve survival in these patients. Although tissue biopsy remains the gold standard for detecting gene mutations, it has limitations, including invasiveness, sampling errors due to tumor heterogeneity, and poor reproducibility.
View Article and Find Full Text PDF