ArticleJournal of experimental & clinical cancer research : CR2022
Cleavage of tropomodulin-3 by asparagine endopeptidase promotes cancer malignancy by actin remodeling and SND1/RhoA signaling.
Article in Journal of experimental & clinical cancer research : CR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 21 citations in OpenAlex.
- Review
- Development and validation of a 5mC-based prognostic model for lung adenocarcinoma survival.Cell reports. Medicine · 2026Article
- Interaction between CDC6 and Tmod3 accelerates resistance to paclitaxel through focal adhesion assembly.Signal transduction and targeted therapy · 2025Article
- Chemotherapeutic drug-triggered AEP-cleaved G3BP1 orchestrates stress granules/nucleoli/mitochondria in osteosarcoma.Bone research · 2025Article
- Targeting PGE2 mediated senescent neuron improves tumor therapy.Neuro-oncology · 2025Article
- Intranasal delivery of AEP inhibitor-loaded neuron-targeted liposome ameliorates radiation-induced brain injury.Materials today. Bio · 2025Article
- Radiotherapy resistance driven by Asparagine endopeptidase through ATR pathway modulation in breast cancer.Journal of experimental & clinical cancer research : CR · 2025Article
- Review
- Proteomic Profiling of Pre- and Post-Surgery Saliva of Glioblastoma Patients: A Pilot Investigation.International journal of molecular sciences · 2024Article
- Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence.iScience · 2024Article
- AEP promotes aberrant RNA splicing through DDX3X cleavage in solid tumors.The Journal of clinical investigation · 2024Article
- AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments.The Journal of clinical investigation · 2023Article
- Asparagine endopeptidase protects podocytes in adriamycin-induced nephropathy by regulating actin dynamics through cleaving transgelin.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- The Mammalian Cysteine Protease Legumain in Health and Disease.International journal of molecular sciences · 2022Review
- Correction: Cleavage of tropomodulin-3 by asparagine endopeptidase promotes cancer malignancy by actin remodeling and SND1/RhoA signaling.Journal of experimental & clinical cancer research : CR · 2022Article
Corrections and comments
- Erratum issued
Authors and funding
14 authors at 6 institutions in 1 country.
Funding
Abstract
backgroundAbnormal proliferation and migration of cells are hallmarks of cancer initiation and malignancy. Asparagine endopeptidase (AEP) has specific substrate cleavage ability and plays a pro-cancer role in a variety of cancers. However, the underlying mechanism of AEP in cancer proliferation and migration still remains unclear.
methodsCo-immunoprecipitation and following mass spectrometry were used to identify the substrate of AEP. Western blotting was applied to measure the expression of proteins. Single cell/nuclear-sequences were done to detect the heterogeneous expression of Tmod3 in tumor tissues. CCK-8 assay, flow cytometry assays, colony formation assay, Transwell assay and scratch wound-healing assay were performed as cellular functional experiments. Mouse intracranial xenograft tumors were studied in in vivo experiments.
resultsHere we showed that AEP cleaved a ubiquitous cytoskeleton regulatory protein, tropomodulin-3 (Tmod3) at asparagine 157 (N157) and produced two functional truncations (tTmod3-N and tTmod3-C). Truncated Tmod3 was detected in diverse tumors and was found to be associated with poor prognosis of high-grade glioma. Functional studies showed that tTmod3-N and tTmod3-C enhanced cancer cell migration and proliferation, respectively. Animal models further revealed the tumor-promoting effects of AEP truncated Tmod3 in vivo. Mechanistically, tTmod3-N was enriched in the cell cortex and competitively inhibited the pointed-end capping effect of wild-type Tmod3 on filamentous actin (F-actin), leading to actin remodeling. tTmod3-C translocated to the nucleus, where it interacted with Staphylococcal Nuclease And Tudor Domain Containing 1 (SND1), facilitating the transcription of Ras Homolog Family Member A/Cyclin Dependent Kinases (RhoA/CDKs).
conclusionThe newly identified AEP-Tmod3 protease signaling axis is a novel "dual-regulation" mechanism of tumor cell proliferation and migration. Our work provides new clues to the underlying mechanisms of cancer proliferation and invasive progression and evidence for targeting AEP or Tmod3 for therapy.
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