{"title":"Dynein: A Multifaceted Therapeutic Target and Its Dysregulation in Aberrant Cell Proliferation.","authors":"Jivesh Garg, Laleh Alisaraie","doi":"10.1002/cm.22041","DOIUrl":"https://doi.org/10.1002/cm.22041","url":null,"abstract":"<p><p>This review examines the diverse functions of dyneins, a family of motor proteins involved in intracellular transport processes, the maintenance of cell polarity, and critical signaling pathways essential for cell cycle progression. Dyneins' significant impact on critical cellular functions is mediated through their interactions with an array of organelles, including centrosomes, chromosomes, and endosomes. Dyneins also influence autophagy and immune evasion within the complex environment of cancer. This review underscores the significance of dyneins as an avenue of exploration for comprehending the intricate mechanisms that underpin cancer.</p>","PeriodicalId":72766,"journal":{"name":"Cytoskeleton (Hoboken, N.J.)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Florian W Hofer, Martin Würtz, Qi Gao, Bram J A Vermeulen, Elmar Schiebel, Stefan Pfeffer
{"title":"Dissecting the Structural Organization, Recruitment and Activation Mechanisms of Centrosomal γ-TuRCs.","authors":"Florian W Hofer, Martin Würtz, Qi Gao, Bram J A Vermeulen, Elmar Schiebel, Stefan Pfeffer","doi":"10.1002/cm.22040","DOIUrl":"https://doi.org/10.1002/cm.22040","url":null,"abstract":"<p><p>Visualizing human centrosomes using cryo-electron tomography revealed the native structure and molecular organization of γ-tubulin ring complexes (γ-TuRCs). γ-TuRCs localized to two distinct centrosomal pools, one in the pericentriolar material (PCM) and another in the centriole lumen, which is released during mitosis. All detected γ-TuRCs were associated with the tetrameric adaptor protein NEDD1. Within the PCM, binding to the centrosomin (CM1) motif of the microcephaly protein CDK5RAP2 in different patterns correlates with conformational changes of γ-TuRCs. In the centriole lumen, the augmin complex anchors γ-TuRCs to the inner scaffold. These observations provide key insights into how the structural organization of γ-TuRCs and regulatory factors collectively govern the spatial and temporal control of microtubule nucleation in centrosomes.</p>","PeriodicalId":72766,"journal":{"name":"Cytoskeleton (Hoboken, N.J.)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marcus A Begley, Taylor Mahoney, Christian Pagán Medina, Parsa Zareiesfandabadi, Matthew B Rapp, Mastawal Tirfe, Sharonda J LeBlanc, Meredith D Betterton, Mary Williard Elting
{"title":"Mechanical Coupling With the Nuclear Envelope Shapes the Schizosaccharomyces pombe Mitotic Spindle.","authors":"Marcus A Begley, Taylor Mahoney, Christian Pagán Medina, Parsa Zareiesfandabadi, Matthew B Rapp, Mastawal Tirfe, Sharonda J LeBlanc, Meredith D Betterton, Mary Williard Elting","doi":"10.1002/cm.22035","DOIUrl":"https://doi.org/10.1002/cm.22035","url":null,"abstract":"<p><p>The fission yeast Schizosaccharomyces pombe divides via closed mitosis, meaning that spindle elongation and chromosome segregation transpire entirely within the closed nuclear envelope. Both the spindle and nuclear envelope must undergo shape changes and exert varying forces on each other during this process. Previous work has demonstrated that nuclear envelope expansion (Yam, He, Zhang, Chiam, & Oliferenko, 2011; Mori & Oliferenko, 2020) and spindle pole body (SPB) embedding in the nuclear envelope are required for normal S. pombe mitosis, and mechanical modeling has described potential contributions of the spindle to nuclear morphology (Fang et al., 2020; Zhu et al., 2016). However, it is not yet fully clear how and to what extent the nuclear envelope and mitotic spindle each directly shape each other during closed mitosis. Here, we investigate this relationship by observing the behaviors of spindles and nuclei in live mitotic fission yeast following laser ablation. First, we characterize these dynamics in mitotic S. pombe nuclei with increased envelope tension, finding that nuclear envelope tension can both bend the spindle and slow elongation. Next, we directly probe the mechanical connection between spindles and nuclear envelopes by ablating each structure. We demonstrate that envelope tension can be relieved by severing spindles and that spindle compression can be relieved by rupturing the envelope. We interpret our experimental data via two quantitative models that demonstrate that fission yeast spindles and nuclear envelopes are a mechanical pair that can each shape the other's morphology.</p>","PeriodicalId":72766,"journal":{"name":"Cytoskeleton (Hoboken, N.J.)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guadalupe E Pena, Xiao Zhou, Lauren Slevin, Christopher Brownlee, Rebecca Heald
{"title":"The NLS3 Motif in TPX2 Regulates Spindle Architecture in Xenopus Egg Extracts.","authors":"Guadalupe E Pena, Xiao Zhou, Lauren Slevin, Christopher Brownlee, Rebecca Heald","doi":"10.1002/cm.22034","DOIUrl":"https://doi.org/10.1002/cm.22034","url":null,"abstract":"<p><p>A bipolar spindle composed of microtubules and many associated proteins functions to segregate chromosomes during cell division in all eukaryotes, yet both spindle size and architecture vary dramatically across different species and cell types. Targeting protein for Xklp2 (TPX2) is one candidate factor for modulating spindle microtubule organization through its roles in branching microtubule nucleation, activation of the mitotic kinase Aurora A, and association with the kinesin-5 (Eg5) motor. Here we characterize a conserved nuclear localization sequence (NLS) motif, <sup>123</sup>KKLK<sup>126</sup> in Xenopus laevis TPX2, which regulates astral microtubule formation and spindle pole morphology in Xenopus egg extracts. Addition of recombinant TPX2 with this sequence mutated to AALA stimulated spontaneous formation of microtubule asters and increased recruitment of phosphorylated Aurora A, pericentrin, and Eg5 to meiotic spindle poles while still binding to the regulatory transport factor importin α. We propose that TPX2 is a linchpin spindle assembly factor whose regulation contributes to the activation of multiple microtubule polymerizing and organizing proteins, generating distinct spindle architectures.</p>","PeriodicalId":72766,"journal":{"name":"Cytoskeleton (Hoboken, N.J.)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Actin-Bundling Protein, Fascin-1, as a Target of Osteoarthritis Progression.","authors":"Rylee E King, Marin Herrick, Justin Parreno","doi":"10.1002/cm.22028","DOIUrl":"https://doi.org/10.1002/cm.22028","url":null,"abstract":"<p><p>The cellular mechanisms underlying osteoarthritis pathogenesis are not fully understood. However, recent in vivo and in vitro studies show that actin cytoskeletal reorganization plays a critical role in the progression of osteoarthritis. It has been shown that targeting the inhibition of actin-bundling protein, fascin, is a favorable way to reorganize actin and prevent chondrocyte dedifferentiation that occurs in osteoarthritis. In a surgical model of osteoarthritis, targeting fascin reduces cartilage degradation and disease severity. These findings highlight the therapeutic potential of targeting fascin in osteoarthritis. Future research to develop a further mechanistic understanding on the critical role actin and actin network molecules play in osteoarthritis may lead to the development of actin-based therapies against disease progression.</p>","PeriodicalId":72766,"journal":{"name":"Cytoskeleton (Hoboken, N.J.)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"PLK4: Master Regulator of Centriole Duplication and Its Therapeutic Potential.","authors":"Muhammad Hamzah, Franz Meitinger, Midori Ohta","doi":"10.1002/cm.22031","DOIUrl":"https://doi.org/10.1002/cm.22031","url":null,"abstract":"<p><p>Centrosomes catalyze the assembly of a microtubule-based bipolar spindle, essential for the precise chromosome segregation during cell division. At the center of this process lies Polo-Like Kinase 4 (PLK4), the master regulator that controls the duplication of the centriolar core to ensure the correct balance of two centrosomes per dividing cell. Disruptions in centrosome number or function can lead to genetic disorders such as primary microcephaly or drive tumorigenesis via centrosome amplification. In this context, several chemical inhibitors of PLK4 have emerged as promising therapeutic candidates. The inhibition of PLK4 results in the emergence of acentrosomal cells, which undergo prolonged and error-prone mitosis. This aberrant mitotic duration triggers a \"mitotic stopwatch\" mechanism that activates the tumor suppressor p53, halting cellular proliferation. However, in a multitude of cancers, the efficacy of this mitotic surveillance mechanism is compromised by mutations that incapacitate p53. Recent investigations have unveiled p53-independent vulnerabilities in cancers characterized by chromosomal gain or amplification of 17q23, which encodes for the ubiquitin ligase TRIM37, in response to PLK4 inhibition, particularly in neuroblastoma and breast cancer. This review encapsulates the latest advancements in our understanding of centriole duplication and acentrosomal cell division in the context of TRIM37 amplification, positioning PLK4 as a compelling target for innovative cancer therapeutics.</p>","PeriodicalId":72766,"journal":{"name":"Cytoskeleton (Hoboken, N.J.)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Inactivation of the Catalytic Activity of Mps1 Kinase Prevents Its Own Degradation at Centrosomes.","authors":"Shrabani Halder, Arpita Dutta, Rupsa Mondal, Banhi Chowdhury, Benu Brata Das, Shubhra Majumder","doi":"10.1002/cm.22032","DOIUrl":"https://doi.org/10.1002/cm.22032","url":null,"abstract":"<p><p>Mps1 kinase plays important roles in regulating centriole assembly, apart from its essential role in spindle assembly checkpoint. Here we report a novel mode of regulating centrosomal Mps1 level, which is governed by its own catalytic activity that promotes its degradation at centrosomes. A kinase-dead mutant of Mps1 or catalytically inactive Mps1 due to treatment with a specific kinase inhibitor is protected from degradation at centrosomes. This autoregulatory mode of controlling Mps1 activity at centrosomes likely restricts excess centriole production in a dividing cell.</p>","PeriodicalId":72766,"journal":{"name":"Cytoskeleton (Hoboken, N.J.)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CEP72 Emerges as a Key Centriolar Satellite Protein in Health and Disease.","authors":"Shweta Tyagi, Aditi Arora, Prajnya Ranganath, Ashwin Dalal","doi":"10.1002/cm.22030","DOIUrl":"https://doi.org/10.1002/cm.22030","url":null,"abstract":"<p><p>Centriolar satellites are membrane-less granules that are now accepted as core structural and functional components of the centrosomes and the cilia. While initially associated with centrosome assembly and primary cilia formation, these complexes and their dynamic structures seem to be involved in various other cellular processes, including protein homeostasis, autophagy, and responses to cellular stress. Since the identification of the first centriolar satellite protein, PCM1, substantial progress has been made in understanding the molecular composition and biological functions of centriolar satellites. Here, we review the function of a centriolar satellite protein CEP72, which is emerging as a key component of many essential processes associated with centrosomes and cilia. We describe the complexes it associates with, their function, and the genetic mutations that implicate CEP72 in a range of human disorders.</p>","PeriodicalId":72766,"journal":{"name":"Cytoskeleton (Hoboken, N.J.)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}