The small-molecule iron transport inhibitor ferristatin/NSC306711 promotes degradation of the transferrin receptor
Graduate School of Biomedical Sciences; Department of Genetics and Complex Diseases
Medical Subject Headings
Biological Transport; Biphenyl Compounds; Cholesterol; Clathrin; Dose-Response Relationship, Drug; Dynamins; *Gene Expression Regulation; Hela Cells; Humans; Iron; Membrane Microdomains; Microscopy, Fluorescence; Models, Chemical; Protein Binding; Receptors, Transferrin; Sulfones
Life Sciences | Medicine and Health Sciences
Iron delivery by transferrin (Tf) is accomplished through clathrin-mediated endocytosis of Tf receptors. The small molecule NSC306711 inhibits iron uptake from the Tf-TfR pathway. Here we show that the drug's mechanism of action is to induce internalization and degradation of unoccupied Tf receptors through an unexpected endocytic pathway. Unlike classical clathrin-mediated Tf receptor endocytosis, internalization promoted by NSC306711 is independent of clathrin and dynamin, and is sensitive to the cholesterol-depleting agents filipin and nystatin. The finding of this cholesterol-dependent Tf receptor internalization pathway through use of the small-molecule inhibitor sheds light on the pleiotropic nature of membrane trafficking dynamics and adds a complex dimension to our understanding of receptor regulation. Because of its unusual properties to inhibit iron uptake, we refer to NSC306711 as "ferristatin."
Rights and Permissions
Citation: Chem Biol. 2008 Jul 21;15(7):647-53. Link to article on publisher's site
Chemistry and biology
Horonchik, Lior and Wessling-Resnick, Marianne, "The small-molecule iron transport inhibitor ferristatin/NSC306711 promotes degradation of the transferrin receptor" (2008). GSBS Student Publications. 1541.