Author:

Keywords:

ACTIVATION, AMYLOID PRECURSOR PROTEIN, ATPASE, Biochemistry & Molecular Biology, DYNAMIC CHANGES, HOMEOSTASIS, iron, ISOFORMS, LATE ENDOSOMES, Life Sciences & Biomedicine, notch, NRAMP2, Science & Technology, SECRETASE, stem cell fate and differentiation, TRAFFICKING, vesicles, divalent metal transporter 1 (Dmt1, Slc11A2, NRAMP2), Humans, Amyloid Precursor Protein Secretases, Cell Line, Iron, Iron-Binding Proteins, Protein Isoforms, Cation Transport Proteins, Regulatory Sequences, Nucleic Acid, 0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3205 Medical biochemistry and metabolomics, 3404 Medicinal and biomolecular chemistry

Abstract:

Notch receptor activation is regulated by the intramembrane protease γ-secretase, which cleaves and liberates the Notch intracellular domain (Nicd) that regulates gene transcription. While γ-secretase cleavage is necessary, we demonstrate it is insufficient for Notch activation and requires vesicular trafficking. Here, we report Divalent metal transporter 1 (Dmt1, Slc11A2) as a novel and essential regulator of Notch signalling. Dmt1-deficient cells are defective in Notch signalling and have perturbed endolysosomal trafficking and function. Dmt1 encodes for two isoforms, with and without an iron response element (ire). We show that isoform-specific silencing of Dmt1-ire and Dmt1+ire has opposite consequences on Notch-dependent cell fates in cell lines and intestinal organoids. Loss of Dmt1-ire suppresses Notch activation and promotes differentiation, whereas loss of Dmt1+ire causes Notch activation and maintains stem-progenitor cell fates. Dmt1 isoform expression correlates with Notch and Wnt signalling in Apc-deficient intestinal organoids and human colorectal cancers. Consistently, Dmt1-ire silencing induces Notch-dependent differentiation in colorectal cancer cells. These data identify Dmt1 isoforms as binary switches controlling Notch cell fate decisions in normal and tumour cells.