Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Más filtros

Banco de datos
Tipo del documento
Asunto de la revista
País de afiliación
Intervalo de año de publicación
1.
J Cell Mol Med ; 24(8): 4668-4676, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32155324

RESUMEN

Class III receptor tyrosine kinases control the development of hematopoietic stem cells. Constitutive activation of FLT3 by internal tandem duplications (ITD) in the juxtamembrane domain has been causally linked to acute myeloid leukaemia. Oncogenic FLT3 ITD is partially retained in compartments of the biosynthetic route and aberrantly activates STAT5, thereby promoting cellular transformation. The pool of FLT3 ITD molecules in the plasma membrane efficiently activates RAS and AKT, which is likewise essential for cell transformation. Little is known about features and mechanisms of FLT3 ligand (FL)-dependent internalization of surface-bound FLT3 or FLT3 ITD. We have addressed this issue by internalization experiments using human RS4-11 and MV4-11 cells with endogenous wild-type FLT3 or FLT3 ITD expression, respectively, and surface biotinylation. Further, FLT3 wild-type, or FLT3 ITD-GFP hybrid proteins were stably expressed and characterized in 32D cells, and internalization and stability were assessed by flow cytometry, imaging flow cytometry, and immunoblotting. FL-stimulated surface-exposed FLT3 WT or FLT3 ITD protein showed similar endocytosis and degradation characteristics. Kinase inactivation by mutation or FLT3 inhibitor treatment strongly promoted FLT3 ITD surface localization, and attenuated but did not abrogate FL-induced internalization. Experiments with the dynamin inhibitor dynasore suggest that active FLT3 as well as FLT3 ITD is largely endocytosed via clathrin-dependent endocytosis. Internalization of kinase-inactivated molecules occurred through a different yet unidentified mechanism. Our data demonstrate that FLT3 WT and constitutively active FLT3 ITD receptor follow, despite very different biogenesis kinetics, similar internalization and degradation routes.


Asunto(s)
Transformación Celular Neoplásica/genética , Leucemia Mieloide Aguda/genética , Proteínas de la Membrana/genética , Factor de Transcripción STAT5/genética , Tirosina Quinasa 3 Similar a fms/genética , Carcinogénesis , Duplicación de Gen/genética , Regulación Neoplásica de la Expresión Génica/genética , Células Madre Hematopoyéticas/patología , Humanos , Leucemia Mieloide Aguda/patología , Ligandos , Mutación , Secuencias Repetidas en Tándem/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA