A Proteostasis Checkpoint Governs EGFR Stability and Cell Fitness, Defined by an lncRNA
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE319594 | GEO | 2026/03/02
REPOSITORIES: GEO
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Project description:The protein abundance of receptor tyrosine kinases such as EGFR is actively maintained under basal conditions by mechanisms that are distinct from ligand-induced signaling and degradation, yet the molecular basis of this regulation remains poorly understood. Here, we identify the long noncoding RNA ERBBride as a critical regulator of EGFR proteostasis. ERBBride binds the EGFR intracellular domain and prevents K48-linked ubiquitination and proteasomal degradation via a UBAP2L-PSMD1 axis. Loss of ERBBride triggers rapid EGFR degradation, robustly reversed by proteasome inhibition, establishing ERBBride as a determinant of receptor stability. This regulation occurs across diverse cancer contexts, irrespective of EGFR mutation, demonstrating mutation-agnostic control of EGFR proteostasis. Despite preserved or even enhanced canonical EGFR signaling outputs, ERBBride depletion selectively impairs EGFR-driven cellular proliferation, including in EGFR-expressing models with oncogenic KRAS backgrounds, revealing that EGFR abundance sustains cell fitness independently of acute canonical signaling. Both genetic depletion and steric-blocking antisense oligonucleotides targeting the ERBBride-EGFR interface reduce tumor growth, providing mechanistic validation and potential therapeutic modulation. Together, these findings define an lncRNA-governed proteostasis checkpoint that controls EGFR stability and cellular fitness, uncovering a previously unappreciated layer of receptor regulation with broad implications for cancer biology and therapy.
2026-02-27 | GSE320026 | GEO
Project description:A Proteostasis Checkpoint Governs EGFR Stability and Cell Fitness, Defined by an lncRNA
| PRJNA1424551 | ENA
Project description:A Proteostasis Checkpoint Governs EGFR Stability and Cell Fitness, Defined by an lncRNA [RNA-seq]
| PRJNA1426010 | ENA
Project description:Background: The lack of obvious symptoms of early gastric cancer (GC) as well as the absence of sensitive and specific biomarkers results in poor clinical outcomes. Tubulin is currently emerging as important regulators of the microtubule cytoskeleton and thus have a strong potential to be implicated in a number of disorders, however, its mechanism of action in gastric cancer is still unclear. Tubulin alpha-1C(TUBA1C) is a subtype of α-tubulin, high TUBA1C expression has been shown to be closely related to a poor prognosis in in various cancers,this study, for the first time, revealed the mechanism of TUBA1C promotes malignant progression of gastric cancer in vitro and in vivo. Methods: The expression of lncRNA EGFR-AS1 was detected in human GC cell lines by qRT–PCR. Mass spectrometry experiments following RNA pulldown assays found that EGFR-AS1 directly binds to TUBA1C, the CCK8, EdU, transwell, wound-healing, cell cycle assays and animal experiments were conducted to investigate the function of TUBA1C in GC. Combined with bioinformatics analyses, reveal interaction between Ki-67, E2F1, PCNA and TUBA1C by western blot. Rescue experiments furtherly demonstrated the relationship of EGFR-AS1and TUBA1C. Results: TUBA1C was proved to be a direct target of EGFR-AS1, TUBA1C promotes gastric cancer proliferation, migration and invasion by accelerating the progression of the cell cycle from the G1 phase to the S phase and activating the expression of oncogenes: Ki-67,E2F1 and PCNA. Conclusions: TUBA1C is a new potential target of LncRNA EGFR-AS1 promotes gastric cancer progression and could be a novel biomarker and therapeutic target for GC.
2023-05-10 | PXD040199 | Pride
Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET. Gene expression profiles were measured in 124 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EGFR-mutation gene expression signature trained in chemo-naive lung adenocarcinoma. The signature was computed as an index, called EGFR index.
2014-06-01 | E-GEOD-31852 | biostudies-arrayexpress
Project description:To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Genetic suppression of EGFR* induction led to significant tumor regression and prolonged survival. But in spite of the initial response, the tumors relapsed invariably and propagated independent of EGFR*. We used microarrys to directly compare geen expression of control and relapse tumors and identified gene sets specifically activated in relapse tumors. Control and relasped glioma samples upon mutant EGFR extinction were selected for RNA extraction and hybridization on Affymetrix microarrays.
2015-01-08 | E-GEOD-64751 | biostudies-arrayexpress
Project description:Intratumoral heterogeneity in EGFR mutant NSCLC results in divergent resistance mechanisms in response to EGFR tyrosine kinase inhibition We used microarrays to investigate the gene expression underlying EGFR TKI resistance with a mesenchymal phenotype.
2016-06-04 | GSE69181 | GEO
Project description:Non-small cell lung cancers (NSCLCs) harboring activating EGFR mutants show dramatic responses to EGFR TKIs, such as erlotinib and geffitinib. However, nearly all patients show relapse within 1 year after initial treatment. We used microarrays to detail global gene expression changes in EGFR mutant cells vs. WT cells responding to erlotinib. 4 EGFR mutant and 4 WT NSCLC cells were treated with or without erlotinib for 24 hr, followed by RNA extraction and hybridization on Affymetrix microarrays.
2014-05-16 | E-GEOD-57156 | biostudies-arrayexpress
Project description:The regulation of proteostasis is fundamental for maintenance of muscle mass and function. Activation of the TGF-β pathway drives wasting and premature aging by favoring the proteasomal degradation of structural muscle proteins. Yet, how this critical post-translational mechanism is kept in check to preserve muscle health remains unclear. Here, we reveal the molecular link between the post-transcriptional regulation of m6A-modified mRNA and the modulation of SMAD-dependent TGF-β signaling. We show that the m6A-binding protein YTHDF2 is essential to determining postnatal muscle size. Indeed, muscle-specific genetic deletion of YTHDF2 impairs skeletal muscle growth and abrogates the response to hypertrophic stimuli. We report that YTHDF2 controls the mRNA stability of the ubiquitin ligase ASB2 with consequences on anti-growth gene program activation through SMAD3. Our study identifies a post-transcriptional to post-translational mechanism for the coordination of gene expression in muscle.
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Project description:The relevance of molecular mechanisms governing mitochondrial proteostasis to the differentiation and function of hematopoietic and immune cells is largely elusive. Through dissection of the network of proteins related to HCLS1-associated protein X-1, we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB. As shown by stable isotope labeling by amino acids in cell culture (SILAC) proteomics, CLPB and HAX1 control the balance of mitochondrial protein synthesis and persistence crucial for proper mitochondrial function. Impaired mitochondrial protein dynamics are associated with decreased abundance of the serine-threonine kinase PRKD2 and HSP27 phosphorylated on serines 78 and 82. Cellular defects in HAX1-/- cells can be functionally reconstituted by HSP27. Thus, mitochondrial proteostasis emerges as a critical molecular and metabolic mechanism governing the differentiation and function of neutrophil granulocytes.
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