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mTORC1-signaling switches megalin function from endocytosis to cell cycle progression.
Cell. Mol. Life Sci. 83:224 (2026)
Mechanistic target of rapamycin (mTOR) signaling pathway controls eukaryotic growth by regulating metabolism, translation, autophagy and cell cycle. Genetic deletion of renal mTORC1 led to a Fanconi-like syndrome with reduction of the renal cortex, tubular epithelial transport and perturbation of the endocytic machinery. Although the main scavenger receptor megalin remained unaltered, a new phosphorylation site at S4577 was found. The identification of the role of this mTORC1-induced phosphorylation on megalin was subject of our analysis. mTORC1-induced megalin phosphorylation reduced endocytosis rate with only minor distribution changes. It augmented the affinity of megalin to the adaptor protein ARH with consecutively increased proteolytic processing of megalin C-terminal domain and favored cell proliferation. During cell mitosis megalin is localized with ARH at the spindle pole. Compared to wildtype cells, megalin-deficient and ARH-deficient cells showed significantly less cell proliferation, and during cytokinesis significantly less ARH or megalin signals, respectively at the pole of intercellular bridges. mTORC1-induced megalin S4577 phopshorylation varies throughout the cell cycle with highest abundance in metaphase and telophase/cytokinesis. Both, lysosomal and non-lysosomal (external) nutrient supply influence cell proliferation to different extent. In conclusion, absence of the mTORC1-induced megalin S4577 phosphorylation favors cell growth and clathrin-mediated endocytosis whereas mTORC1-induced megalin phosphorylation at S4577 favors cell proliferation and increases the affinity to the adaptor protein ARH for proper cell division. Especially, during cytokinesis megalin and ARH ensure trafficking of membrane vesicles towards the pole of intercellular bridges most probably for the terminal abscission process.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Clathrin ; Kidney ; Lrp2 ; Metaphase ; Proteolytical Cleavage ; Proximal Tubule; Regulated Intramembrane Proteolysis; Proximal Tubule; Mediated Endocytosis; Protein; Clathrin; Expression; Transport; Growth
ISSN (print) / ISBN
1420-682X
e-ISSN
1420-9071
Quellenangaben
Volume: 83,
Issue: 1,
Article Number: 224
Publisher
Springer
Publishing Place
Picassoplatz 4, Basel, 4052, Switzerland
Reviewing status
Peer reviewed
Institute(s)
CF Metabolomics & Proteomics (CF-MPC)
Grants
Christian-Albrechts-Universitt zu Kiel (3094)