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La señalización de Wnt requiere el secuestro de la glicogénica sintetasa quinasa 3 dentro de los endosomas
Vincent F Taelman1, Radoslaw Dobrowolski, Jean-Louis Plouhinec
1Howard Hughes Medical Institute and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA.
Cell
|December 25, 2010
Resumen
La señalización Wnt secuestra la Glicogén Sintasa Kinasa 3 (GSK3) en cuerpos multivesiculares, reduciendo su actividad. Esta secuestración es crucial para la función de la vía Wnt y estabiliza otras proteínas.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- La señalización Wnt canónica es una vía crítica en el desarrollo y la enfermedad.
- La inhibición de la Glycogen Synthase Kinase 3 (GSK3) es esencial para la activación de la vía Wnt.
- El mecanismo molecular preciso para la inhibición de GSK3 durante la señalización Wnt no se entiende completamente.
Objetivo del estudio:
- Para dilucidar el mecanismo molecular por el cual la señalización de Wnt inhibe la actividad de la Glycogen Synthase Kinase 3 (GSK3).
- Para investigar el papel del tráfico endosómico en la transducción de la señal Wnt.
Principales métodos:
- Estudios de co-localización de Wnt y GSK3 en compartimentos endosómicos.
- Medición de la actividad de GSK3 en el citosol.
- Pruebas de protección de proteasa para evaluar la localización de GSK3.
- Microscopía cryo-inmunoelectrónica para el análisis ultrastructural.
- Manipulación genética de proteínas involucradas en la formación de cuerpos multivesiculares (MVB) (HRS/Vps27, Vps4).
Principales resultados:
- La señalización Wnt induce el secuestro de GSK3 en cuerpos multivesiculares (MVB).
- El Wnt endocitado se colocaliza con GSK3 en vesículas endosomales ácidas.
- La actividad de GSK3 en el citosol disminuye con la adición de Wnt, y GSK3 se protege dentro de los orgánulos unidos a la membrana.
- Las proteínas de formación de MVB HRS/Vps27 y Vps4 son necesarias para la señalización Wnt.
- La secuestración GSK3 estabiliza la β-catenina y otras proteínas citosólicas, incluida una proteína reportera.
Conclusiones:
- Los endosomas multivesiculares son componentes esenciales de la vía de transducción de señales Wnt.
- La señalización Wnt inhibe la actividad de GSK3 secuestrándola en MVBs, separándola así de sustratos citosólicos.
- Este mecanismo explica cómo la señalización Wnt logra la inhibición de GSK3 y regula los objetivos posteriores.
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