Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor.
J Exp Med
; 215(2): 661-679, 2018 02 05.
Article
en En
| MEDLINE
| ID: mdl-29282252
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores de Eritropoyetina
/
Proteínas Supresoras de Tumor
/
Péptidos y Proteínas de Señalización Intracelular
/
Eritropoyesis
/
Hierro
/
Proteínas de la Membrana
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Exp Med
Año:
2018
Tipo del documento:
Article
País de afiliación:
Ciudad del Vaticano