10 results on '"Anvarian Z"'
Search Results
2. Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?
- Author
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Rüdiger Stefan GD, Anvarian Zeinab, Minde David P, and Maurice Madelon M
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Summary Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene strongly predispose to development of gastro-intestinal tumors. Central to the tumorigenic events in APC mutant cells is the uncontrolled stabilization and transcriptional activation of the protein β-catenin. Many questions remain as to how APC controls β-catenin degradation. Remarkably, the large C-terminal region of APC, which spans over 2000 amino acids and includes critical regions in downregulating β-catenin, is predicted to be natively unfolded. Here we discuss how this uncommonly large disordered region may help to coordinate the multiple cellular functions of APC. Recently, a significant number of germline and somatic missense mutations in the central region of APC were linked to tumorigenesis in the colon as well as extra-intestinal tissues. We classify and localize all currently known missense mutations in the APC structure. The molecular basis by which these mutations interfere with the function of APC remains unresolved. We propose several mechanisms by which cancer-related missense mutations in the large disordered domain of APC may interfere with tumor suppressor activity. Insight in the underlying molecular events will be invaluable in the development of novel strategies to counter dysregulated Wnt signaling by APC mutations in cancer.
- Published
- 2011
- Full Text
- View/download PDF
3. DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2.
- Author
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Rezi CK, Aslanyan MG, Diwan GD, Cheng T, Chamlali M, Junger K, Anvarian Z, Lorentzen E, Pauly KB, Afshar-Bahadori Y, Fernandes EF, Qian F, Tosi S, Christensen ST, Pedersen SF, Strømgaard K, Russell RB, Miner JH, Mahjoub MR, Boldt K, Roepman R, and Pedersen LB
- Subjects
- Animals, Mice, Humans, Protein Transport, Mice, Knockout, Kidney metabolism, Epithelial Cells metabolism, Protein Binding, Vesico-Ureteral Reflux metabolism, Vesico-Ureteral Reflux genetics, Membrane Proteins metabolism, Membrane Proteins genetics, Urogenital Abnormalities, Cilia metabolism, TRPP Cation Channels metabolism, TRPP Cation Channels genetics, Discs Large Homolog 1 Protein metabolism, Carrier Proteins metabolism, Carrier Proteins genetics
- Abstract
Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we describe a role for DLG1, a core component of the Scribble polarity complex, in regulating ciliary protein trafficking in kidney epithelial cells. Conditional knockout of Dlg1 in mouse kidney causes ciliary elongation and cystogenesis, and cell-based proximity labeling proteomics and fluorescence microscopy show alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer-associated protein SDCCAG3, IFT20, and polycystin-2 (PC2) are reduced in the cilia of DLG1-deficient cells compared to control cells. This phenotype is recapitulated in vivo and rescuable by re-expression of wild-type DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggest that SDCCAG3 and IFT20 form a complex that associates, at least indirectly, with DLG1. Our work identifies a key role for DLG1 in regulating ciliary protein composition and suggests that ciliary dysfunction of the p.T489R DLG1 variant may contribute to CAKUT., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
4. Transient accumulation and bidirectional movement of KIF13B in primary cilia.
- Author
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Juhl AD, Anvarian Z, Kuhns S, Berges J, Andersen JS, Wüstner D, and Pedersen LB
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Biological Transport, Cytoskeletal Proteins metabolism, Flagella metabolism, Humans, Microtubules, Cilia metabolism, Kinesins genetics
- Abstract
Primary cilia are microtubule-based sensory organelles whose assembly and function rely on the conserved bidirectional intraflagellar transport (IFT) system, which is powered by anterograde kinesin-2 and retrograde cytoplasmic dynein-2 motors. Nematodes additionally employ a cell-type-specific kinesin-3 motor, KLP-6, which moves within cilia independently of IFT and regulates ciliary content and function. Here, we provide evidence that a KLP-6 homolog, KIF13B, undergoes bursts of bidirectional movement within primary cilia of cultured immortalized human retinal pigment epithelial (hTERT-RPE1) cells. Anterograde and retrograde intraciliary velocities of KIF13B were similar to those of IFT (as assayed using IFT172-eGFP), but intraciliary movement of KIF13B required its own motor domain and appeared to be cell-type specific. Our work provides the first demonstration of motor-driven, intraciliary movement by a vertebrate kinesin other than kinesin-2 motors., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
5. A targeted multi-proteomics approach generates a blueprint of the ciliary ubiquitinome.
- Author
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Aslanyan MG, Doornbos C, Diwan GD, Anvarian Z, Beyer T, Junger K, van Beersum SEC, Russell RB, Ueffing M, Ludwig A, Boldt K, Pedersen LB, and Roepman R
- Abstract
Establishment and maintenance of the primary cilium as a signaling-competent organelle requires a high degree of fine tuning, which is at least in part achieved by a variety of post-translational modifications. One such modification is ubiquitination. The small and highly conserved ubiquitin protein possesses a unique versatility in regulating protein function via its ability to build mono and polyubiquitin chains onto target proteins. We aimed to take an unbiased approach to generate a comprehensive blueprint of the ciliary ubiquitinome by deploying a multi-proteomics approach using both ciliary-targeted ubiquitin affinity proteomics, as well as ubiquitin-binding domain-based proximity labelling in two different mammalian cell lines. This resulted in the identification of several key proteins involved in signaling, cytoskeletal remodeling and membrane and protein trafficking. Interestingly, using two different approaches in IMCD3 and RPE1 cells, respectively, we uncovered several novel mechanisms that regulate cilia function. In our IMCD3 proximity labeling cell line model, we found a highly enriched group of ESCRT-dependent clathrin-mediated endocytosis-related proteins, suggesting an important and novel role for this pathway in the regulation of ciliary homeostasis and function. In contrast, in RPE1 cells we found that several structural components of caveolae (CAV1, CAVIN1, and EHD2) were highly enriched in our cilia affinity proteomics screen. Consistently, the presence of caveolae at the ciliary pocket and ubiquitination of CAV1 specifically, were found likely to play a role in the regulation of ciliary length in these cells. Cilia length measurements demonstrated increased ciliary length in RPE1 cells stably expressing a ubiquitination impaired CAV1 mutant protein. Furthermore, live cell imaging in the same cells revealed decreased CAV1 protein turnover at the cilium as the possible cause for this phenotype. In conclusion, we have generated a comprehensive list of cilia-specific proteins that are subject to regulation via ubiquitination which can serve to further our understanding of cilia biology in health and disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Aslanyan, Doornbos, Diwan, Anvarian, Beyer, Junger, van Beersum, Russell, Ueffing, Ludwig, Boldt, Pedersen and Roepman.)
- Published
- 2023
- Full Text
- View/download PDF
6. Angiomotin isoform 2 promotes binding of PALS1 to KIF13B at primary cilia and regulates ciliary length and signaling.
- Author
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Morthorst SK, Nielsen C, Farinelli P, Anvarian Z, Rasmussen CBR, Serra-Marques A, Grigoriev I, Altelaar M, Fürstenberg N, Ludwig A, Akhmanova A, Christensen ST, and Pedersen LB
- Subjects
- Cilia metabolism, Guanylate Kinases, Hedgehog Proteins metabolism, Protein Isoforms, Angiomotins, Membrane Proteins metabolism
- Abstract
The kinesin-3 motor KIF13B functions in endocytosis, vesicle transport and regulation of ciliary length and signaling. Direct binding of the membrane-associated guanylate kinase (MAGUK) DLG1 to the MAGUK-binding stalk domain of KIF13B relieves motor autoinhibition and promotes microtubule plus-end-directed cargo transport. Here, we characterize angiomotin (AMOT) isoform 2 (p80, referred to as Ap80) as a novel KIF13B interactor that promotes binding of another MAGUK, the polarity protein and Crumbs complex component PALS1, to KIF13B. Live-cell imaging analysis indicated that Ap80 is concentrated at and recruits PALS1 to the base of the primary cilium, but is not a cargo of KIF13B itself. Consistent with a ciliary function for Ap80, its depletion led to elongated primary cilia and reduced agonist-induced ciliary accumulation of SMO, a key component of the Hedgehog signaling pathway, whereas Ap80 overexpression caused ciliary shortening. Our results suggest that Ap80 activates KIF13B cargo binding at the base of the primary cilium to regulate ciliary length, composition and signaling., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
7. Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network.
- Author
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Anvarian Z, Nojima H, van Kappel EC, Madl T, Spit M, Viertler M, Jordens I, Low TY, van Scherpenzeel RC, Kuper I, Richter K, Heck AJ, Boelens R, Vincent JP, Rüdiger SG, and Maurice MM
- Subjects
- Amino Acid Sequence, Animals, Axin Protein analysis, Axin Protein ultrastructure, Cell Line, Drosophila chemistry, Drosophila genetics, Drosophila metabolism, Drosophila ultrastructure, Drosophila Proteins analysis, Drosophila Proteins genetics, Drosophila Proteins metabolism, HEK293 Cells, Humans, Mice, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Neoplasms metabolism, Neoplasms pathology, Protein Conformation, Protein Interaction Maps, Scattering, Small Angle, Sequence Alignment, X-Ray Diffraction, Axin Protein genetics, Axin Protein metabolism, Neoplasms genetics, Point Mutation, Protein Aggregates, Wnt Signaling Pathway
- Abstract
Signaling cascades depend on scaffold proteins that regulate the assembly of multiprotein complexes. Missense mutations in scaffold proteins are frequent in human cancer, but their relevance and mode of action are poorly understood. Here we show that cancer point mutations in the scaffold protein Axin derail Wnt signaling and promote tumor growth in vivo through a gain-of-function mechanism. The effect is conserved for both the human and Drosophila proteins. Mutated Axin forms nonamyloid nanometer-scale aggregates decorated with disordered tentacles, which 'rewire' the Axin interactome. Importantly, the tumor-suppressor activity of both the human and Drosophila Axin cancer mutants is rescued by preventing aggregation of a single nonconserved segment. Our findings establish a new paradigm for misregulation of signaling in cancer and show that targeting aggregation-prone stretches in mutated scaffolds holds attractive potential for cancer treatment.
- Published
- 2016
- Full Text
- View/download PDF
8. Maternal Wnt/STOP signaling promotes cell division during early Xenopus embryogenesis.
- Author
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Huang YL, Anvarian Z, Döderlein G, Acebron SP, and Niehrs C
- Subjects
- Animals, Cell Cycle, Fertilization, Glycogen Synthase Kinase 3 beta, Humans, Mitosis, Oocytes cytology, Protein Array Analysis, Signal Transduction, Transcription, Genetic, Gene Expression Regulation, Developmental, Glycogen Synthase Kinase 3 metabolism, Wnt1 Protein metabolism, Xenopus Proteins metabolism, Xenopus laevis embryology
- Abstract
During Xenopus development, Wnt signaling is thought to function first after midblastula transition to regulate axial patterning via β-catenin-mediated transcription. Here, we report that Wnt/glycogen synthase kinase 3 (GSK3) signaling functions posttranscriptionally already in mature oocytes via Wnt/stabilization of proteins (STOP) signaling. Wnt signaling is induced in oocytes after their entry into meiotic metaphase II and declines again upon exit into interphase. Wnt signaling inhibits Gsk3 and thereby protects proteins from polyubiquitination and degradation in mature oocytes. In a protein array screen, we identify a cluster of mitotic effector proteins that are polyubiquitinated in a Gsk3-dependent manner in Xenopus. Consequently inhibition of maternal Wnt/STOP signaling, but not β-catenin signaling, leads to early cleavage arrest after fertilization. The results support a novel role for Wnt signaling in cell cycle progression independent of β-catenin.
- Published
- 2015
- Full Text
- View/download PDF
9. Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?
- Author
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Minde DP, Anvarian Z, Rüdiger SG, and Maurice MM
- Subjects
- Adenomatous Polyposis Coli genetics, Adenomatous Polyposis Coli metabolism, Adenomatous Polyposis Coli Protein chemistry, Adenomatous Polyposis Coli Protein genetics, Adenomatous Polyposis Coli Protein physiology, Animals, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Genes, Tumor Suppressor, Humans, Models, Biological, Protein Folding, Protein Structure, Tertiary physiology, Genes, APC physiology, Mutation, Missense physiology, Neoplasms genetics
- Abstract
Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene strongly predispose to development of gastro-intestinal tumors. Central to the tumorigenic events in APC mutant cells is the uncontrolled stabilization and transcriptional activation of the protein β-catenin. Many questions remain as to how APC controls β-catenin degradation. Remarkably, the large C-terminal region of APC, which spans over 2000 amino acids and includes critical regions in downregulating β-catenin, is predicted to be natively unfolded. Here we discuss how this uncommonly large disordered region may help to coordinate the multiple cellular functions of APC. Recently, a significant number of germline and somatic missense mutations in the central region of APC were linked to tumorigenesis in the colon as well as extra-intestinal tissues. We classify and localize all currently known missense mutations in the APC structure. The molecular basis by which these mutations interfere with the function of APC remains unresolved. We propose several mechanisms by which cancer-related missense mutations in the large disordered domain of APC may interfere with tumor suppressor activity. Insight in the underlying molecular events will be invaluable in the development of novel strategies to counter dysregulated Wnt signaling by APC mutations in cancer.
- Published
- 2011
- Full Text
- View/download PDF
10. Identification of a new site of sumoylation on Tel (ETV6) uncovers a PIAS-dependent mode of regulating Tel function.
- Author
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Roukens MG, Alloul-Ramdhani M, Vertegaal AC, Anvarian Z, Balog CI, Deelder AM, Hensbergen PJ, and Baker DA
- Subjects
- Amino Acid Sequence, Animals, Biopolymers, Bone Neoplasms metabolism, Bone Neoplasms pathology, Cell Line, Tumor metabolism, Conserved Sequence, Humans, Lysine chemistry, Molecular Sequence Data, Osteosarcoma metabolism, Osteosarcoma pathology, Proto-Oncogene Proteins c-ets physiology, Repressor Proteins physiology, Sequence Alignment, Sequence Homology, Amino Acid, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Vertebrates genetics, Vertebrates metabolism, ETS Translocation Variant 6 Protein, Molecular Chaperones physiology, Protein Inhibitors of Activated STAT physiology, Protein Processing, Post-Translational physiology, Proto-Oncogene Proteins c-ets chemistry, Repressor Proteins chemistry, SUMO-1 Protein metabolism, Small Ubiquitin-Related Modifier Proteins metabolism
- Abstract
Cell proliferation and differentiation are governed by a finely controlled balance between repression and activation of gene expression. The vertebrate Ets transcriptional repressor Tel (ETV6) and its invertebrate orthologue Yan, play pivotal roles in cell fate determination although the precise mechanisms by which repression of gene expression by these factors is achieved are not clearly defined. Here, we report the identification and characterization of the primary site of sumoylation of Tel, lysine 11 (K11), which is highly conserved in vertebrates (except Danio rerio). We demonstrate that in cells PIAS3 binds to Tel and stimulates sumoylation of K11 in the nucleus. Both Tel monomers and oligomers are efficiently sumoylated on K11 in vitro; but in cells only Tel oligomers are found conjugated with SUMO, whereas sumoylation of Tel monomers is transitory and appears to sensitize them for proteasomal degradation. Mechanistically, sumoylation of K11 inhibits repression of gene expression by full-length Tel. In accordance with this observation, we found that sumoylation impedes Tel association with DNA. By contrast, a Tel isoform lacking K11 (TelM43) is strongly repressive. This isoform results from translation from an alternative initiation codon (M43) that is common to all Tel proteins that also contain the K11 sumoylation consensus site. We find that PIAS3 may have a dual, context-dependent influence on Tel; it mediates Tel sumoylation, but it also augments Tel's repressive function in a sumoylation-independent fashion. Our data support a model that suggests that PIAS-mediated sumoylation of K11 and the emergence of TelM43 in early vertebrates are linked and that this serves to refine spatiotemporal control of gene expression by Tel by establishing a pool of Tel molecules that are available either to be recycled to reinforce repression of gene expression or are degraded in a regulated fashion.
- Published
- 2008
- Full Text
- View/download PDF
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