Spatial centrosome proteome of human neural cells uncovers novel interactors and disease hubs
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA833732 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19309800_1.fastq.gz | Fastqsanger.gz | |||
| SRR19309800_2.fastq.gz | Fastqsanger.gz | |||
| SRR19309801_1.fastq.gz | Fastqsanger.gz | |||
| SRR19309801_2.fastq.gz | Fastqsanger.gz | |||
| SRR19309796_1.fastq.gz | Fastqsanger.gz |
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Project description:Despite the crucial importance of the centrosome in brain development and disease, its comprehensive proteome remains uncharacterized in neural cells. Here, we used spatial proteomics to elucidate protein interaction networks at the centrosome of iPSC-derived human neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell-type specific, with protein hubs involved in RNA-dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant splicing factor PRPF6 reproduced the periventricular misplacement in the developing mouse brain, highlighting mis-splicing of transcripts of the MAP-kinase SAD-A at centrosomal location as essential for the phenotype. Collectively, cell-type specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.
2022-06-15 | GSE201954 | GEO
Project description:Despite the crucial importance of the centrosome in brain development and disease, its comprehensive proteome remains uncharacterized in neural cells. Here, we used spatial proteomics to elucidate protein interaction networks at the centrosome of iPSC-derived human neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type-specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant splicing factor PRPF6 reproduced the periventricular misplacement in the developing mouse brain, highlighting mis-splicing of transcripts of the MAP-kinase SAD-A at centrosomal location as essential for the phenotype. Collectively, cell type-specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.
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Project description:A large number of cancer-associated proteins involved in the cell cycle, DNA repair, chaperoning and nucleocytoplasmic transport etc. are involved in the control of centrosome number, duplication, centrosome formation and have been implicated as origin of centrosome abnormalities in cancer. In this study, we performed gene expression profiling with focusing on centrosome-related genes for determining the molecular signature characteristic for centrosome abnormalities in MM patients.
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Project description:Centrosome amplification induces proliferation arrest and cell invasion. The fate of centrosome amplification cells are studied here.
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Project description:Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB2 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.
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Project description:Stringent control of centrosome duplication and separation is important for preventing chromosome instability. Structural and numerical alterations in centrosomes are hallmarks of neoplastic cells and contribute to tumorigenesis. We show that a Centrosome Amplification 20 (CA20) gene signature is associated with high expression of the Tripartite Motif (TRIM) family member E3 ubiquitin ligase, TRIM69. TRIM69-ablation in cancer cells leads to centrosome scattering and chromosome segregation defects. To identify potential effectors of TRIM69 in regulating centrosome dynamics, we performed mass-spectrometry analysis of immunopurified TRIM69 complexes and defined the TRIM69 protein-interaction network. We discovered Serine/threonine-protein kinase 3 (MST2) as a new direct binding partner of TRIM69 and TRIM69 redistributes MST2 to the perinuclear cytoskeleton. Additionally, we performed IP mass- spectrometry analysis to define the MST2 interactome in the presence and absence of co-expressed TRIM69A. We found that WT TRIM69A (but not the E3 ligase mutant) promoted complex formation between MST2 and PLK1 in the detergent-insoluble CSK compartment. PLK1-mediated phosphorylation of MST2 at S15, S18 and S316 is crucial for centrosome disjunction. Analysis of MST2 phospho-peptides from the LC-MS/MS experiment revealed increased phosphorylation of S15, S316 and several other residues in the detergent-insoluble fraction of TRIM69A-overexpressing cells. Our findings suggest that TRIM69 is a new proximal regulator of distinct signaling pathways that regulate centrosome dynamics and promote bipolar mitosis. Further studies are necessary to identify the putative TRIM69A substrate(s) whose ubiquitination is necessary for regulating and interacting MST2 and centrosome dynamics. To address this issue, we have performed an unbiased mass spectrometry screen for TRIM69A-induced ubiquitination events.
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Project description:Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB2 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation. genome-wide human SNP 6.0 arrays from Affymetrix was used to determine the copy number changes of MCF10A cells with extra centrosomes or depleted of MCAK after grown 4 days in 3-D cultures
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Project description:Centrosomal protein 120 (CEP120) is a 120kD centrosome protein that plays an important role in centrosome replication. Overexpression of CEP120 can lead to centrosome amplification, which is closely associated with tumorigenesis and development. However, there are no reports on the relationship between CEP120 and tumors. In our study, overexpression of CEP120 promoted centrosome amplification in gastric cancer (GC), and the role of CEP120 in promoting GC progression was demonstrated in vitro and in vivo. We demonstrated that CEP120 promotes centrosome amplification and GC progression by promoting the expression and centrosome aggregation of the deubiquitinating enzyme USP54, maintaining the stability of PLK4 and reducing its ubiquitination degradation. In conclusion, the CEP120-USP54-PLK4 axis may play an important role in promoting centrosome amplification and GC progression, thus providing a potential therapeutic target for GC.
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