FBXO44 Regulates Rac1 Spatiotemporal Dynamics: An Exploitable Therapeutic Vulnerability for Actin Cytoskeleton-Targeted Treatment in Gastric Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1237828 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32757737_1.fastq.gz | Fastqsanger.gz | |||
| SRR32757737_2.fastq.gz | Fastqsanger.gz | |||
| SRR32757738_1.fastq.gz | Fastqsanger.gz | |||
| SRR32757738_2.fastq.gz | Fastqsanger.gz | |||
| SRR32757739_1.fastq.gz | Fastqsanger.gz |
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Project description:The dynamic homeostasis of the cytoskeleton represents a critical vulnerability in tumor cells, yet the molecular mechanisms governing this equilibrium remain elusive. In the present study, we identify FBXO44 as a crucial regulator of Rac1 nucleocytoplasmic shuttling through its interaction with MTSS1. In gastric cancer (GC), FBXO44 orchestrates dual ubiquitination programs on MTSS1: K63-linked polyubiquitination promotes Rac1 nuclear translocation to drive cytoskeletal remodeling, whereas K11-linked modification triggers MTSS1 proteasomal degradation to restrict Rac1 nuclear trafficking. Structural analysis reveals that FBXO44 engages MTSS1 through distinct domains, dynamically balancing these opposing ubiquitination events through precise control MTSS1 protein levels, thereby calibrating actin cytoskeletal dynamics. Clinically, this regulatory axis maintains an oncogenic equilibrium-FBXO44 overexpression correlates with Rac1 signaling activation in progressive GC patients. Therapeutically, pharmacological disruption of this balance using the novel inhibitor DQ2405 achieves dual anti-tumor effects: suppressing tumor growth and metastatic capacity. Our findings establish FBXO44-mediated Rac1 spatiotemporal control as a druggable strategy for actin-cytoskeleton targeted therapy, providing both mechanistic insights into cytoskeletal homeostasis and a translational framework for GC treatment.
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Project description:Spermatogenesis is a biological process within the testis that produces haploid spermatozoa for the continuity of species. Sertoli cells are somatic cells in the seminiferous epithelium that orchestrate spermatogenesis. Cyclic reorganization of Sertoli cell actin cytoskeleton is vital for spermatogenesis but the underlying mechanism remains largely unclear. Here we report that RNA-binding protein PTBP1 controls Sertoli cell actin cytoskeleton reorganization by programming alternative splicing of actin cytoskeleton regulators. This splicing control enables ectoplasmic specializations, the actin-based adhesion junctions, to maintain the blood-testis barrier and support spermatid transport and transformation. Of particular, we show that PTBP1 promotes actin bundle formation by repressing the inclusion of exon 14 of Tnik, a kinase present at the ectoplasmic specialization. Our results thus reveal a novel mechanism wherein Sertoli cell actin cytoskeleton dynamics is controlled post-transcriptionally by utilizing functionally distinct isoforms of actin regulatory proteins and PTBP1 is a key player in generating such isoforms.
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Project description:We describe a new mutant allele of the ACTIN2 gene with enhanced actin dynamics, displaying a broad array of twisting and bending phenotypes that resemble BR-treated plants. Moreover, auxin transcriptional regulation is enhanced on the mutant background, supporting the idea that shaping actin filaments is sufficient to modulate BR-mediated auxin responsiveness. The actin cytoskeleton thus functions as a scaffold for integration of auxin and BR signaling pathways.
2012-11-21 | GSE27077 | GEO
Project description:We describe a new mutant allele of the ACTIN2 gene with enhanced actin dynamics, displaying a broad array of twisting and bending phenotypes that resemble BR-treated plants. Moreover, auxin transcriptional regulation is enhanced on the mutant background, supporting the idea that shaping actin filaments is sufficient to modulate BR-mediated auxin responsiveness. The actin cytoskeleton thus functions as a scaffold for integration of auxin and BR signaling pathways. Three biological replicates were performed for each sample (wild-type and actin2-5) and hybridized to the the Affymetrix ATH1 GeneChips.
2012-11-21 | E-GEOD-27077 | biostudies-arrayexpress
Project description:PTBP1 mediates Sertoli cell actin cytoskeleton organization through regulating alternative splicing of actin regulators
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Project description:Ubiquitin-dependent remodeling of the actin cytoskeleton drives cell fusion
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Project description:Cell-cell fusion is a frequent and essential event during development, and its dysregulation causes diseases ranging from infertility to muscle weakness. Fusing cells repeatedly need to remodel their plasma membrane by orchestrated formation and disassembly of cortical actin filaments, but how the dynamic reorganization of the actin cytoskeleton control is still poorly understood. Here, we identified a ubiquitin- dependent toggle switch that establishes reversible actin bundling during mammalian cell fusion. We found that EPS8-IRSp53 complexes stabilize cortical actin bundles at sites of cell contact, which in part pushes cells towards each other. Conversely, EPS8 monoubiquitylation by CUL3KCTD10 displaces EPS8-IRSp53 from membranes and counteracts actin bundling, a dual activity that allows apposed cells to progress with fusion. We conclude that cytoskeletal rearrangements during development are precisely controlled by ubiquitylation, raising the possibility to modulate the efficiency of cell-cell fusion for therapeutic benefit.
2020-12-22 | GSE161681 | GEO
Project description:The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energy-consuming material with dynamic properties shaping the structure and function of the cell. The proper function of actin is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis (1–5). The breakdown of these cellular processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton (5–9). However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well understood. Here, we performed a multi-pronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo C. elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator promoting actin health and longevity. Interestingly, overexpression of bet-1 preserves actin health at late age and promotes lifespan and healthspan in C. elegans. These beneficial effects are through preservation of actin, downstream of the function of BET-1 as a transcriptional regulator. Together, our discovery attributes assigns a key role of BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.
2023-06-01 | E-MTAB-12289 | biostudies-arrayexpress
Project description:The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energy-consuming material with dynamic properties shaping the structure and function of the cell. The proper function of actin is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis (1–5). The breakdown of these cellular processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton (5–9). However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well understood. Here, we performed a multi-pronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo C. elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator promoting actin health and longevity. Interestingly, overexpression of bet-1 preserves actin health at late age and promotes lifespan and healthspan in C. elegans. These beneficial effects are through preservation of actin, downstream of the function of BET-1 as a transcriptional regulator. Together, our discovery attributes assigns a key role of BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.
2023-06-01 | E-MTAB-11786 | biostudies-arrayexpress
Project description:Amplification of the Melanocortin-1 Receptor in Nephrotic Syndrome Renders a Good Target for Podocyte Cytoskeleton Stabilization During the last years, several reports have been presented of beneficial effects of ACTH in patients with nephrotic syndrome. Among the known ACTH receptors, the melanocortin-1 receptor (MC1R) has been suggested as the mediator of the ACTH renoprotective effect with the mechanism of action resulting in stabilization of the actin cytoskeleton in podocytes. To understand how melanocortin receptors are regulated in nephrotic syndrome and how they are involved in restoration of filtration barrier function, melanocortin receptor expression was evaluated in patients and in a rat model of nephrotic syndrome in combination with cell culture analysis. Phosphoproteomic mass spectrometry was applied and identified MC1R pathways confirmed using biochemical analysis. We found that glomerular MC1R expression was increased in nephrotic syndrome, both in humans and in a rat model. A MC1R agonist protected podocytes from protamine sulfate induced stress fiber loss with the top ranked phoshoproteomic MC1R activated pathway beeing actin cytoskeleton signaling. Actin stabilization through the MC1R consisted of ERK1/2 dependent phosphorylation and inactivation of EGFR signaling with stabilization of synaptopodin and stress fibers in podocytes. These results further explain how patients with nephrotic syndrome show responsiveness to ACTH treatment by depressing EGFR signaling through activation of the MC1R receptor and as a consequence restore filtration barrier function by stabilizing the podocyte actin cytoskeleton.
2019-11-12 | PXD009198 | Pride