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.
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.
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
Rxiv cytoskeleton
Rxiv mechanobio