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La activación de Aurora A dependiente de HEF1 induce el desmontaje del cilium primario
Elena N Pugacheva1, Sandra A Jablonski, Tiffiney R Hartman
1Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Cell
|July 3, 2007
Resumen
Los cilios de los mamíferos, sensores celulares cruciales, se desmontan a través de una vía que involucra a HEF1 y la aurora A (AurA) quinasa, activando HDAC6. Este descubrimiento revela un nuevo papel para AurA y sugiere objetivos terapéuticos para trastornos relacionados con los cilios.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- Los cilios de los mamíferos son sensores celulares vitales involucrados en numerosos procesos de desarrollo y patológicos.
- Los defectos en las vías de señalización asociadas a los cilios están vinculados a varios trastornos.
- Los mecanismos que rigen la formación y el desmontaje del cilio siguen siendo en gran medida desconocidos.
Objetivo del estudio:
- Para dilucidar los mecanismos celulares que controlan el desmontaje ciliar.
- Identificar proteínas y vías clave involucradas en la resorción ciliar.
- Explorar posibles estrategias terapéuticas dirigidas a la estabilidad ciliar.
Principales métodos:
- Interacciones de proteínas investigadas en el cuerpo basal de los cilios.
- Utilizó ensayos bioquímicos para evaluar la fosforilación de proteínas y la actividad enzimática.
- Empleó inhibidores de moléculas pequeñas para modular la actividad de la vía.
- Efectos observados en la estructura ciliar y la estabilidad en modelos celulares.
Principales resultados:
- La proteína prometastática HEF1 interactúa con la aurora A (AurA) quinasa en el cuerpo basal del cilio.
- Esta interacción conduce a la fosforilación y activación de HDAC6, una desacetilasa de la tubulina.
- La activación de HDAC6 promueve el desmontaje ciliar (resorción).
- Esta vía es necesaria y suficiente para la resorción ciliar, lo que representa una función no mitótica de AurA.
Conclusiones:
- Una nueva vía que involucra a HEF1, AurA y HDAC6 regula el desmontaje ciliar de los mamíferos.
- La Aurora A quinasa posee un inesperado papel no mitótico en el control de la resorción ciliar.
- Los inhibidores de AurA y HDAC6 pueden estabilizar los cilios, lo que sugiere posibles aplicaciones clínicas para el tratamiento de trastornos relacionados con la disfunción ciliar.
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