ArticleInternational journal of molecular sciences2022
Exclusion of NUMB Exon12 Controls Cancer Cell Migration through Regulation of Notch1-SMAD3 Crosstalk.
Article in International journal of molecular sciences, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 8 citations in OpenAlex.
- Multi-omics identifies VMP1 as a tumor-intrinsic biomarker associated with metastatic progression and immune microenvironment remodeling in HNSCC.Translational oncology · 2026Article
- RBFOX2-dependent alternative splicing of Numb regulates Notch signaling during muscle stem cell activation.Stem cell reports · 2026Article
- MRAS: Master Regulator Analysis of Alternative Splicing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Article
- Numb and NumbL inhibit melanoma tumor growth by influencing the immune microenvironment.BMC cancer · 2024Article
- Expression and clinical significance of Numb and Notch-1 proteins between tissue of colon cancer and regional lymph node metastases.Frontiers in oncology · 2024Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
NUMB is an endocytic adaptor protein that contains four isoforms (p65, p66, p71 and p72) due to alternative splicing regulation. Here, we show that NUMB exon12 (E12)-skipping isoforms p65/p66 promote epithelial to mesenchymal transition (EMT) and cancer cell migration in vitro, and facilitate cancer metastasis in mice, whereas E12-included p71/p72 isoforms attenuate these effects. Mechanistically, p65/p66 isoforms significantly increase the sorting of Notch1 through early endosomes (EEs) for enhanced Notch1 activity. In contrast, p71/p72 isoforms act as negative regulators of Notch1 by ubiquitylating the Notch1 intracellular domain (N1ICD) and promoting its degradation. Moreover, we observed that the interaction between N1ICD and SMAD3 is important for their own stabilization, and for NUMB-mediated EMT response and cell migration. Either N1ICD or SMAD3 overexpression could significantly recuse the migration reduction seen in the p65/p66 knockdown, and Notch1 or SMAD3 knockdown rescued the migration advantage seen in the overexpression of p66. Taken all together, our study provides mechanistic insights into the opposite regulation of Notch1-SMAD3 crosstalk by NUMB isoforms and identifies them as critical regulators of EMT and cancer cell migration.
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Registered trials
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