Ask about this productRelated genes to: PIK3R4 Blocking Peptide
- Gene:
- PIK3R4 NIH gene
- Name:
- phosphoinositide-3-kinase regulatory subunit 4
- Previous symbol:
- -
- Synonyms:
- VPS15, p150
- Chromosome:
- 3q22.1
- Locus Type:
- gene with protein product
- Date approved:
- 2000-04-11
- Date modifiied:
- 2015-11-17
Related products to: PIK3R4 Blocking Peptide
Related articles to: PIK3R4 Blocking Peptide
- Esophageal cancer (EC) remains an extremely lethal cancer with few prognostic biomarkers and specific therapies. Although autophagy is increasingly recognized as a key force behind tumor adaptation and resistance to therapy, its systematic role at the EC progression level for prognostics, as well as for drug target prediction, remains unclear. Here, we attempted to build a systems-wide map linking autophagy- and signaling-related genes and transcriptional dysregulation, patient survival, and druggability in EC. Hub genes were found using an integrative bioinformatics pipeline based on protein-protein interaction networks and further explored using enrichment, expression, survival, and molecular docking analyses. Functional enrichment highlighted autophagy, mitophagy, ferroptosis, and immune signaling as central processes, converging with stress- and metabolism-associated pathways. Expression profile of TCGA-ESCA data demonstrated substantial overexpression of autophagy initiators and elongation factors (ATG3, ATG5, ATG7, ATG12, ATG13), upstream regulators (AMBRA1, UVRAG), and stress/metabolic mediators (TP53, MYD88, GAPDH). Kaplan-Meier analysis indicated three genes, including ATG4A, GABARAPL2, and GAPDH, that exhibited significant expression levels correlating with less survival and emphasizing their prognostic capacities. Screening for drugs also revealed AKT1, TP53, and PIK3R4 as druggable hubs, and many drugs (e.g., Everolimus, Dabrafenib, Trabectedin) showing high-affinity interactions. These findings collectively demonstrate that the progression of EC is supported by a coordinated program that integrates autophagy and metabolic reprogramming with stress and immunological signaling. The study discovers new prognostic markers (ATG4A, GABARAPL2, GAPDH) and druggable targets, which could lead to better risk stratification and smarter drug repurposing. While restricted to in silico analyses, the integrative approach provides a basis for subsequent laboratory confirmation and translational development. - Source: PubMed
Publication date: 2026/05/27
Salehi ShirinMottaghi-Dastjerdi NegarShahbazi BehzadAhmadi NahidGhorbani AbozarSoltany-Rezaee-Rad MohammadYazdani FatemeKhoshdel FarzaneNiazi Mohammad-Javad - Delayed cerebral ischaemia (DCI) is a major determinant of poor clinical outcome after aneurysmal subarachnoid haemorrhage (aSAH), but its underlying mechanisms are not fully understood. We aimed to perform a genome-wide association study (GWAS) in aSAH patients with and without DCI. We conducted a multicentre study of European ancestry within the International Stroke Genetics Consortium with two stages: Stage 1 (n = 1,085; four centres) and Stage 2 (n = 801; one centre). A GWAS meta-analysis was performed across both stages. We then examined whether variants associated with DCI were linked to differences in gene expression (expression quantitative trait loci, eQTLs) or DNA methylation (methylation quantitative trait loci, mQTLs) and validated the methylation findings in an aSAH cohort with available DNA methylation data (n = 344). We performed complementary postGWAS analysis in order to promote biological interpretation of the genome-wide findings, including the genetic overlap with ischaemic stroke and intracranial aneurysm (ruptured and unruptured) using publicly available published GWAS summary statistics. Among 1,879 patients with DCI data, the prevalence of DCI was 22.8% (428/1,879). In the meta-analysis across both stages, we identified one genome-wide significant variant, rs7636350 (Chr3:130328911:T:C), associated with an increased risk of DCI (additive OR 1.75 [95% CI 1.43-2.13], P=4.47×10⁻⁸). This variant mapped near the COL6A6 and PIK3R4 genes. Functional annotation revealed one significant eQTL for PIK3R4 and one mQTL for cg23181900, located within COL6A6. Hypermethylation at cg23181900 was associated with DCI in a cohort with DNA methylation data (logFC=0.016, 95% CI 0.002-0.032; P=0.0317). Genetic correlation analyses showed a marginal correlation with ischaemic stroke due to large artery atherosclerosis (r=0.172; P=0.0508) and a higher correlation with intracranial aneurysm (r=0.341; P=0.002). We identified a genome-wide significant locus associated with DCI after aSAH, implicating COL6A6 and PIK3R4. We additionally identified an mQTL at cg23181900, suggesting a regulatory link at this locus. These findings enhance our understanding of DCI pathophysiology and support further studies to clarify causality and determine whether these pathways may inform future therapeutic strategies. - Source: PubMed
Publication date: 2026/05/26
Jiménez-Balado JoanArreaza-Baena MarcBakker Mark KRuigrok Ynte MVallverdú-Prats MartaOis AngelMacias-Gómez AdriàFernández-Pérez IsabelGuisado-Alonso DanielRodriguez-Campello AnaGiralt-Steinhauer EvaJiménez-Conde JordiBijlenga PhilippeMorel SandrineRezai Jahromi BehnamNiemelä MikaWerring David JHostettler Isabel CCuadrado-Godia Elisa - Cell mechanics can serve as an important biomarker for cell state and phenotype, such as metastatic ability. While some molecular mechanisms underlying cell mechanical properties have been investigated through targeted analyses, a genome-wide study of human genes and gene networks that modulate cell biophysical properties has not been attempted. In this work, we combined a microfluidic stiffness-based sorting device with a genome-scale CRISPR knockout (GeCKO) screen in order to investigate the effect of individual gene knockouts on cell stiffening and cell softening across the entire protein-coding genome. We processed approximately 150 million Cas9-expressing ovarian cancer cells that had been transduced with a library of 76,000 single guide RNAs (sgRNAs) against the 19,000 protein-coding genes in the genome. The cells were sorted into 5 mechanical subsets. We identified 7 gene knockouts that were significantly depleted in the softer subsets and over 700 gene knockouts that were significantly enriched in the stiffer subsets. Of these significant genes of interest, we selected 3 genes that were highly expressed in our ovarian cancer cell line with greater than 100-fold enrichment in the stiff outlet and resulted in significant changes in ovarian cancer patient survival. These genes, and , when knocked out result in a significant and predicted increase in cell stiffness. This study is the first to explore the relation between human gene expression and cell mechanics at the genome-scale to generate datasets at the intersection between cell genotype, mechanotype, and phenotype for metastatic cancer cells. The method could also be applied to study the effect of genes on other biophysical cell processes as well as for identifying pathways for the control of cellular mechanics across many cell types. - Source: PubMed
Publication date: 2026/02/12
Young Katherine MDobrowolski CurtisStone NicholasPaunovska KalinaBules SydneyAhkee KellyHankish JamesChapman AlexDahlman James ESulchek Todd AReinhart-King Cynthia A - Increasing availability and utilisation of high-throughput sequencing techniques has resulted in a rapidly expanding range of uterine mesenchymal lesions harbouring recurrent and nonrecurrent gene rearrangements. Within the literature, 3 molecularly confirmed FOXO1 -rearranged uterine corpus tumors have been reported, all representing alveolar rhabdomyosarcomas (ARMS). We report 5 cases of non-ARMS uterine mesenchymal tumors, in patients aged 36 to 71, harbouring novel FOXO1 rearrangements with different fusion partners ( JRK , PIK3R4, MEIS1 , and ATP7B); in the fifth case, FISH revealed a FOXO1 gene rearrangement with an unknown fusion partner. Although morphologically heterogenous, all 5 cases had a low-grade spindle cell component with 3 cases showing prominent myxoid stroma. Two cases were originally diagnosed as myxoid leiomyosarcoma, one as high-grade endometrial stromal sarcoma, one as an undifferentiated sarcoma with a fibrosarcoma-like appearance, and the other as a myxoid neoplasm of uncertain malignant potential. In 3 cases, the rearrangements showed similar breakpoints to known recurrent FOXO1 gene fusions; 2 rearrangements ( JRK::FOXO1 and MEIS1::FOXO1 ) incorporate both an intact transactivation domain and a DNA-binding domain akin to the rearrangements seen in ARMS, likely representing true oncogenic driver events. Although all 5 cases were confined to the uterine corpus at presentation, recurrences occurred in 2 patients indicating a potential for malignant behaviour and justifying the designation of sarcoma. These cases expand the landscape of FOXO1 -rearranged neoplasms and describe a potential new uterine mesenchymal entity. Further study of additional cases is needed to establish whether these rearrangements truly represent an initiating event for a distinct subset of uterine sarcomas, or whether FOXO1 rearrangements simply represent an additional noninitiating/nondriver event within other established tumor types. - Source: PubMed
Publication date: 2025/12/11
Pilkington ThomasWatt ChrisDermawan JosephineHaider AsmaAgaimy AbbasHowitt Brooke EChiang SarahAntonescu CristinaMcCluggage W Glenn - The mammalian class III phosphatidylinositol-3-kinase complex (PtdIns3K) forms two biochemically and functionally distinct subcomplexes including the ATG14-containing complex I (PtdIns3K-C1) and the UVRAG-containing complex II (PtdIns3K-C2). Both subcomplexes adopt a V-shaped architecture with a BECN1-ATG14 or UVRAG adaptor arm and a PIK3R4/VPS15-PIK3C3/VPS34 catalytic arm. NRBF2 is a pro-autophagic modulator that specifically associates with PtdIns3K-C1 to enhance its kinase activity and promotes macroautophagy/autophagy. How NRBF2 exerts such a positive effect is not fully understood. Here we report that NRBF2 binds to PIK3R4/VPS15 with moderate affinity through a conserved site on its N-terminal MIT domain. The NRBF2-PIK3R4/VPS15 interaction is incompatible with the UVRAG-containing PtdIns3K-C2 because the C2 domain of UVRAG outcompetes NRBF2 for PIK3R4/VPS15 binding. Our crystal structure of the NRBF2 coiled-coil (CC) domain reveals a symmetric homodimer with multiple hydrophobic pairings at the CC interface, which is in distinct contrast to the asymmetric dimer observed in the yeast ortholog Atg38. Mutations in the CC domain that rendered NRBF2 monomeric led to weakened binding to PIK3R4/VPS15 and only partial rescue of autophagy deficiency in knockout cells. In comparison, NRBF2 with its CC domain replaced by a dimeric Gcn4 module showed proautophagic activity comparable to wild type while NRBF2 carrying a tetrameric Gcn4 module showed further enhanced activity. We propose that the oligomeric state of NRBF2 mediated by its CC domain is critical for strengthening the moderate NRBF2-PIK3R4/VPS15 interaction mediated by its MIT domain to fully activate PtdIns3K-C1 and promote autophagy. ATG: autophagy related; ATG14: autophagy related 14; BECN1: beclin 1; CC: coiled-coil; dCCD: delete CCD; dMIT: delete MIT; Gcn4: general control nonderepressible 4; ITC: isothermal titration calorimetry; IP: immunoprecipitation; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MIM: MIT-interacting motif; MIT: microtubule interacting and trafficking; NMR: nuclear magnetic resonance; NRBF2: nuclear receptor binding factor 2; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; VPS: vacuolar protein sorting; WT: wild type. - Source: PubMed
Publication date: 2025/11/12
Li NaLi XiaohuaQiu XianxiuPan XuehuaWu ShuaiChen JingyiLiu RongLu JiahongYue ZhenyuZhao Yanxiang