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Fbxl13 regulates centrosome homeostasis and migration through ubiquitin mediated proteolysis

ABSTRACT: F-box proteins are the variable substrate adaptor subunits of the SCF (Skp1, Cul1, F-box) ubiquitin ligases. The family comprise about 69 members with important roles in cancer pathogenesis and cell proliferation. Among the F-box proteins, Fbxl13 is frequently amplified in several cancer patient cohorts suggesting an important role in promoting cancer pathogenesis. However, the main function of Fbxl13 is unknown and its biochemical mechanism of action remains uncharacterised. Here, we show that Fbxl13 specifically interacts with the centrosomal proteins Centrin-2, Centrin-3, Cep152, and Cep192. Fbxl13 is enriched at the centrosome, where it targets Cep192 for ubiquitin mediated proteolysis. In line with this, Fbxl13 overexpression downregulated centrosomal γ-tubulin, and disrupted centrosomal microtubule arrays. Furthermore, depletion of Fbxl13 in U2OS cells corresponds to defects in centrosome duplication and cell motility. Thus, we propose that Fbxl13 is a novel regulator of centrosome duplication and microtubule nucleation activity, highlighting a potential tumourigenic role of Fbxl13 in promoting cell motility.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Philip Charles

LAB HEAD: Benedikt Kessler

PROVIDER: PXD006756 | Pride | 2022-03-02

REPOSITORIES: Pride

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FBXL13 regulates centrosome homeostasis and migration through ubiquitin- mediated proteolysis

Project description:Aberrant centrosome organization with ensuing alterations of microtubule nucleation enables tumor cells to proliferate and invade despite increased genomic instability. CEP192 is a key factors in the initiation process of centrosome duplication and in the control of centrosome microtubule nucleation. However, regulatory means of CEP192 have remained unknown. Here we report that FBXL13, a binding determinant of SCF (SKP1-CUL1-F-Box)-family E3 ubiquitin ligases, is enriched at centrosomes and interacts with the centrosomal proteins Centrin-2, Centrin-3, CEP152, and CEP192. Among these, CEP192 is specifically targeted for proteasomal degredation by FBXL13. Accordingly, induced FBXL13 expression downregulates centrosomal γ-tubulin, and disrupts centrosomal microtubule arrays. In addition, depletion of FBXL13 induces high levels of CEP192 and γ-tubulin at the centrosomes corresponding to defects in cell motility. Together, we characterize FBXL13 as a novel regulator of microtubule nucleation activity and highlight a role in promoting cell motility with potential tumor-promoting implications.

2018-01-16 | PXD008310 | Pride

CEP120 Promotes Centrosome Amplification And Progression Of Gastric Cancer Via USP54-Mediated Deubiquitination Of PLK4

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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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Oncogene-like induction of cellular invasion from centrosome amplification

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2017-03-15 | E-MTAB-2827 | biostudies-arrayexpress

Spatial centrosome proteome of human neural cells uncovers novel interactors and disease hubs

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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