Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor
| Autor: | Yukio Nakamura, Maja Holy, Ryo Kurita, Stephen Grado, Lorrie Delehanty, Grant C. Bullock, Adam N. Goldfarb, Shadi Khalil, Katie Freeman, Zollie White |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Isocitrates Iron Immunology Transferrin receptor Nutrient sensing Models Biological Article Cell Line 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Receptors Transferrin medicine Receptors Erythropoietin Immunology and Allergy Animals Humans Erythropoiesis Progenitor cell Receptor Protein kinase B Research Articles Erythroid Precursor Cells Chemistry Protein Stability Tumor Suppressor Proteins Intracellular Signaling Peptides and Proteins Membrane Proteins Cathepsins Cell biology Erythropoietin receptor Mice Inbred C57BL 030104 developmental biology Erythropoietin 030220 oncology & carcinogenesis medicine.drug |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 |
| Popis: | Iron deficiency causes resistance in erythroid progenitors against proliferative but not survival signals of erythropoietin. Khalil et al. link this response to the down-regulation of Scribble, an orchestrator of receptor trafficking and signaling. With iron deprivation, transferrin receptor 2 drives Scribble degradation, reconfiguring erythropoietin receptor function. Iron-restricted human anemias are associated with the acquisition of marrow resistance to the hematopoietic cytokine erythropoietin (Epo). Regulation of Epo responsiveness by iron availability serves as the basis for intravenous iron therapy in anemias of chronic disease. Epo engagement of its receptor normally promotes survival, proliferation, and differentiation of erythroid progenitors. However, Epo resistance caused by iron restriction selectively impairs proliferation and differentiation while preserving viability. Our results reveal that iron restriction limits surface display of Epo receptor in primary progenitors and that mice with enforced surface retention of the receptor fail to develop anemia with iron deprivation. A mechanistic pathway is identified in which erythroid iron restriction down-regulates a receptor control element, Scribble, through the mediation of the iron-sensing transferrin receptor 2. Scribble deficiency reduces surface expression of Epo receptor but selectively retains survival signaling via Akt. This mechanism integrates nutrient sensing with receptor function to permit modulation of progenitor expansion without compromising survival. |
| Databáze: | OpenAIRE |
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