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
- 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 - Probiotics are beneficial microorganisms that modulate various signaling pathways to improve human health status. In this study we aimed to evaluate the precise molecular effects of Lactobacillus spp., Bifidobacterium spp., and a mixture of our native potential probiotics on the autophagy signaling pathway during the presence of inflammation. The evaluation of autophagy gene expression was performed after exposing the HT -29 cell line with the sonicated pathogens and probiotics, before and simultaneously with inflammation induction by quantitative real-time polymerase chain reaction (qPCR) and cytokine assays. The results of the current study showed that our native potential probiotic cocktails could upregulate the expression level of the autophagy genes including pik3c3, atg14, beclin, pik3r4, atg5, atg16, atg7, and atg3 compared with sonicated pathogen treatments, and also these native potential probiotic strains could exert anti-inflammatory effects, especially before inflammation induction. In conclusion, our native potential probiotic cocktail indicated the preventive and therapeutic effect on inflammation, but our selected probiotics could affect autophagy genes stronger before inflammation compared to expose simultaneously with inflammation. Therefore, the administration of probiotics as a prophylactic agent with the least side effects could be considered a suitable treatment for patients with inflammatory-related disease, even before or at the beginning of inflammation. - Source: PubMed
Publication date: 2025/07/11
Jouriani Fatemeh HaririzadehTorkamaneh MahdiTorfeh MahnazAshrafian FatemehAghamohammad ShadiRohani Mahdi - Reduced autophagy is associated with the aberrant humoral response observed in lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency; however, the molecular mechanisms and their impact on T-cell responses remain poorly understood. We identify two novel LRBA interactors, phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4) and FYVE And Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1), which each play key roles in autophagy. PIK3R4 facilitates the production of phosphatidylinositol-3 phosphate (PI(3)P) that promotes autophagosome formation and autophagosome-lysosome fusion, whereas FYCO1 supports autophagosome movement. LRBA-knockout (KO) cells show impaired PI(3)P production, reduced autophagosome-lysosome fusion, accumulation of enlarged autophagosomes, and decreased cargo degradation. In line with the role of autophagy as a major degradation system for MHC-II loading and antigen presentation, we observe increased numbers of MHC class II and LC3 vesicles, along with enhanced antigen presentation in absence of LRBA, resulting in a higher production of proinflammatory cytokines from T cells in vitro. Our work suggests a novel biological role of LRBA controlling antigen presentation and T-cell responses by positively regulating autophagy, which may contribute to T-cell immune dysregulation observed in LRBA-deficient patients. - Source: PubMed
Publication date: 2025/06/23
Sindram ElenaDeau Marie-CelineLigeon Laure-AnneSanchez-Martin PabloNestel SigrunJung SophieRuf StefanieMishra PankajProietti MicheleGünther StefanThedieck KathrinRoussa EleniRambold AngelikaMünz ChristianKraft ClaudineGrimbacher BodoGámez-Díaz Laura