The benefits of local depletion: The centrosome as a scaffold for ubiquitin-proteasome-mediated degradation

Vora, Setu M.; Phillips, Bryan T.

doi:10.1080/15384101.2016.1196306

Cited by 32 publications

(42 citation statements)

References 101 publications

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“…Given the central role of CEP192 in centrosome evolution and biogenesis, a comprehensive functional analysis of this protein will allow us to decipher how the centrosome nucleates MTs and to gain invaluable insights into other functions of this still mysterious organelle. It seems particularly important to decipher the link between centrosomes and cell cycle regulation, DNA repair, proteostasis, and innate immune responses (402,409,(418)(419)(420)(421).…”

Section: Discussionmentioning

confidence: 99%

Aurora-PLK1 cascades as key signaling modules in the regulation of mitosis

Joukov¹,

2018

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Mitosis is controlled by reversible protein phosphorylation involving specific kinases and phosphatases. A handful of major mitotic protein kinases, such as the cyclin B-CDK1 complex, the Aurora kinases, and Polo-like kinase 1 (PLK1), cooperatively regulate distinct mitotic processes. Research has identified proteins and mechanisms that integrate these kinases into signaling cascades that guide essential mitotic events. These findings have important implications for our understanding of the mechanisms of mitotic regulation and may advance the development of novel antimitotic drugs. We review collected evidence that in vertebrates, the Aurora kinases serve as catalytic subunits of distinct complexes formed with the four scaffold proteins Bora, CEP192, INCENP, and TPX2, which we deem "core" Aurora cofactors. These complexes and the Aurora-PLK1 cascades organized by Bora, CEP192, and INCENP control crucial aspects of mitosis and all pathways of spindle assembly. We compare the mechanisms of Aurora activation in relation to the different spindle assembly pathways and draw a functional analogy between the CEP192 complex and the chromosomal passenger complex that may reflect the coevolution of centrosomes, kinetochores, and the actomyosin cleavage apparatus. We also analyze the roles and mechanisms of Aurora-PLK1 signaling in the cell and centrosome cycles and in the DNA damage response.

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Section: Discussionmentioning

confidence: 99%

Aurora-PLK1 cascades as key signaling modules in the regulation of mitosis

Joukov¹,

2018

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“…Though this may not necessarily be physiologically compatible, we observed a positive correlation in cells exhibiting aggregates and enrichment at centriole. Interestingly, subunits as well as substrates of proteosomal complexes have also been demonstrated to be enriched at the centriole (50). Given the proposed unstable nature of ASH-RhoGAP mutants, it is tempting to speculate that this enrichment is due to these misfolded or unstable proteins being targeted for degradation by the centriole-associated proteasome aka 'aggresome' (51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

Genotype & Phenotype in Lowe Syndrome: SpecificOCRL1patient mutations differentially impact cellular phenotypes

Ramadesikan¹,

Skiba²,

Lee³

et al. 2020

Preprint

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Lowe Syndrome (LS) is a lethal genetic disorder caused by mutations in the OCRL1 gene, which encodes the lipid 5’ phosphatase Ocrl1. Patients exhibit a characteristic triad of symptoms including eyes, brain and kidneys abnormalities with renal failure as the most common cause of death. Over 200 OCRL1 mutations have been identified in LS, but their specific impact on cellular processes is unknown. Despite observations of heterogeneity in LS patient symptoms, there is little understanding of the correlation between the genotype of patients and disease and/or cellular phenotypes.Here, we showed that different mutations had diverse effects on protein localization, stability and on triggering LS cellular phenotypes. In addition, mutations in specific domains imparted unique characteristics to the resulting mutated protein. We also propose that some mutations conformationally affect the 5’-phosphatase domain of the protein, resulting in additional phenotypes and loss of activity.This study is the first to show the differential effect of patient 5’-phosphatase mutations on cellular phenotypes and introduces a conformational disease component in LS. This work can provide a framework that can help stratify patients as well as provide a more accurate prognosis depending on the nature and location of the mutation in the OCRL1 gene and its effect on the biochemical activity of Ocrl1.

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“…Both the rapid turnover of centrosomal SYS-1 in wild-type cells and the reliance of centrosomal localization for negative regulation implicate a proteolysis mechanism, such as proteasomal degradation, that is linked to the centrosome. Additionally, proteasome components and proteasomal clients localize to centrosomes in C. elegans and other systems (Vora and Phillips, 2015, Vora and Phillips, 2016, Fabunmi et al, 2000, Wigley et al, 1999). To test the idea that the proteasome regulates centrosomal SYS-1, we inhibited proteasomal degradation in C. elegans embryos and found increased SYS-1 centrosomal levels, but decreased SYS-1 turnover in FRAP analyses.…”

Section: Wβa Linkage To the Cell Cycle Provides Robustness For Celmentioning

confidence: 99%

Wnt Signaling Polarizes C. elegans Asymmetric Cell Divisions During Development

Lam

Phillips

2017

Results and Problems in Cell Differentiation

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Asymmetric cell division is a common mode of cell differentiation during the invariant lineage of the nematode, C. elegans. Beginning at the four-cell stage, and continuing throughout embryogenesis and larval development, mother cells are polarized by Wnt ligands, causing an asymmetric inheritance of key members of a Wnt/β-catenin signal transduction pathway termed the Wnt/β-catenin asymmetry pathway. The resulting daughter cells are distinct at birth with one daughter cell activating Wnt target gene expression via β-catenin activation of TCF, while the other daughter displays transcriptional repression of these target genes. Here, we seek to review the body of evidence underlying a unified model for Wnt-driven asymmetric cell division in C. elegans, identify global themes that occur during asymmetric cell division as well as highlight tissue-specific variations. We also discuss outstanding questions that remain unanswered regarding this intriguing mode of asymmetric cell division.

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The benefits of local depletion: The centrosome as a scaffold for ubiquitin-proteasome-mediated degradation

Cited by 32 publications

References 101 publications

Aurora-PLK1 cascades as key signaling modules in the regulation of mitosis

Aurora-PLK1 cascades as key signaling modules in the regulation of mitosis

Genotype & Phenotype in Lowe Syndrome: SpecificOCRL1patient mutations differentially impact cellular phenotypes

Wnt Signaling Polarizes C. elegans Asymmetric Cell Divisions During Development

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