Cytoplasmic Fidgetin Induces Noncanonical Activation of β-catenin to Support Cancer Progression
Abstract. The subcellular localization, together with the expression level, determines the biological effects and physiological functions of proteins. Fidgetin (FIGN) is a microtubule-severing protein that plays a critical role in cytoskeletal dynamics, and it predominantly localizes in the nucleus in normal cells. Here, we observed FIGN largely in the cytoplasm of malignant cells, and increased cytoplasmic FIGN was significantly associated with clinicopathological features and poor prognosis in breast carcinoma, hepatocellular carcinoma and lung adenocarcinoma. Cytoplasmic FIGN promoted tumor development, growth, and metastasis in multiple mouse models, and it facilitated proliferation, colony formation, migration, and invasion of multiple cancer cells in vitro. FIGN interacted with MYH2 and HNRNPA2B1; MYH2 regulated the nucleocytoplasmic distribution of FIGN and its effects on cancer progression, while cytoplasmic FIGN stabilized β-catenin mRNA and promoted malignant biological behaviors in an HNRNPA2B1-dependent manner. Furthermore, an iRGD-fused peptide was designed to block the MYH2-FIGN interface, which facilitated FIGN translocation to the nucleus and suppressed cancer progression. Together, this study demonstrates a noncanonical mechanism for β-catenin activation by cytoplasmic FIGN that drives cancer progression.
Cytoplasmic Fidgetin Induces Noncanonical Activation of β-catenin to Support Cancer Progression
Abstract. The subcellular localization, together with the expression level, determines the biological effects and physiological functions of proteins. Fidgetin (FIGN) is a microtubule-severing protein that plays a critical role in cytoskeletal dynamics, and it predominantly localizes in the nucleus in normal cells. Here, we observed FIGN largely in the cytoplasm of malignant cells, and increased cytoplasmic FIGN was significantly associated with clinicopathological features and poor prognosis in breast carcinoma, hepatocellular carcinoma and lung adenocarcinoma. Cytoplasmic FIGN promoted tumor development, growth, and metastasis in multiple mouse models, and it facilitated proliferation, colony formation, migration, and invasion of multiple cancer cells in vitro. FIGN interacted with MYH2 and HNRNPA2B1; MYH2 regulated the nucleocytoplasmic distribution of FIGN and its effects on cancer progression, while cytoplasmic FIGN stabilized β-catenin mRNA and promoted malignant biological behaviors in an HNRNPA2B1-dependent manner. Furthermore, an iRGD-fused peptide was designed to block the MYH2-FIGN interface, which facilitated FIGN translocation to the nucleus and suppressed cancer progression. Together, this study demonstrates a noncanonical mechanism for β-catenin activation by cytoplasmic FIGN that drives cancer progression.
📰 "Identification of feeding apparatus components in a heterotrophic marine flagellate"
https://www.biorxiv.org/content/10.64898/2026.03.30.714256v1?rss=1 #Microtubule
Identification of feeding apparatus components in a heterotrophic marine flagellate
Acquiring nutrients is a fundamental biological process of all organisms, playing crucial roles in ecological sustainability. Diplonemids are highly abundant heterotrophic unicellular flagellates that are widespread in the world's ocean. They have a highly complex microtubule-based feeding apparatus (cytostome-cytopharynx complex) located adjacent to the deep flagellar pocket from which two flagella emerge from parallel basal bodies. The apical papilla is a tongue-shaped structure unique to diplonemids that connects the cytopharynx and the flagellar pocket, the latter of which is formed by reinforcing microtubules (MTR) and two flagellar roots called intermediate and dorsal roots. Here we report identification of 17 proteins that localize at the feeding apparatus or flagellar apparatus in Diplonema papillatum . Using ultrastructure expansion microscopy, we show that Mad2 and its interaction partner MBP65 localize at the MTR, intermediate root, and dorsal root. Homologs of proteins that associate with the flagellar apparatus in Trypanosoma brucei (PFR2, KMP11, BILBO1) localize at the feeding apparatus in D. papillatum . We also identify proteins that localize at the apical papilla, MTR, parallel microtubule loop, or cytopharynx. By discovering components of the feeding apparatus for the first time in diplonemids, this work forms the foundation to understand molecular mechanisms of the feeding apparatus in these highly abundant marine plankton.
### Competing Interest Statement
The authors have declared no competing interest.
Wellcome Trust, 227243/Z/23/Z, 226791
📰 "Tau-induced elevation in promoter-proximal RNA polymerase II pausing is linked to decreased expression of long neuronal genes in a Drosophila tauopathy model."
https://www.biorxiv.org/content/10.64898/2026.03.28.709859v1?rss=1 #Microtubule
Tau-induced elevation in promoter-proximal RNA polymerase II pausing is linked to decreased expression of long neuronal genes in a Drosophila tauopathy model.
Tauopathies, including Alzheimers disease, are age-related neurodegenerative disorders characterized by abnormal phosphorylation and buildup of microtubule-associated protein tau. Gene expression dysregulation is a key molecular feature of tauopathies, but how aging and disease interact to disrupt crucial transcriptional regulators and pathways remains largely unknown. Here, we examined how pathological tau affects gene expression programs in age-related neurodegenerative disease using a well-established Drosophila melanogaster tauopathy model with neuronal expression of the toxic human tauR406W. Transcriptomic analysis of tau-expressing fly heads showed a preferential downregulation of long neuronal genes with long introns. Notably, we found that these downregulated genes in the tauopathy model are marked by increased accumulation of initiating RNA polymerase II (RNAP II) near the transcription start site and reduced elongating RNAP II within gene bodies, indicating a problem with the transition from initiation to elongation. By calculating an RNAP II Pause Index (PI) for each gene, we identified a strong link between promoter-proximal RNAP II stalling, gene expression deficits, and gene length in the tauopathy model. Overall, we have uncovered the genomic and transcriptomic features of tau-dependent downregulated genes and identified increased RNAP II promoter-proximal stalling as a significant mechanism of transcription stress in tauopathy.
### Competing Interest Statement
The authors have declared no competing interest.
NIH Common Fund, https://ror.org/001d55x84, 1R21AG077058-01, 5R01NS135611-03
Expanding the C. elegans toolkit with gonad explants
Animal development is a complex process that requires the coordination of a plethora of pathways in space and time. In several species, the availability of tissue explants has provided a simplified context that facilitates mechanistic investigations, particularly into dynamic events. Here, we demonstrate that extruded C. elegans gonads are a viable tissue explant system for this model organism. Using live-cell imaging, we show that C. elegans gonad explants retain many tissue properties that have been documented in vivo, including mitosis, meiosis, apoptosis and gametogenesis. We further show that C. elegans explants are acutely responsive to treatment by the microtubule depolymerizing drug nocodazole. Our work thus reveals C. elegans gonad explants as a new system in which live-cell imaging and acute drug treatment can be combined to decipher the mechanisms governing germline development.
### Competing Interest Statement
The authors have declared no competing interest.
Canadian Institutes of Health Research, PJT-525829
📰 "Reversibly unlocking the blood-brain barrier: A study on microtubule dynamics modulation using gold nanoparticle-modified reduced graphene oxide"
https://doi.org/doi:10.1016/j.apsb.2025.12.015https://pubmed.ncbi.nlm.nih.gov/41909741/ #Microtubule
Rxiv mechanobio
Rxiv cytoskeleton