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Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
Published on: March 9, 2012
La transducción de señales mediada por integrina está vinculada a la vía Ras mediante la unión de GRB2 a la cinasa de
D D Schlaepfer1, S K Hanks, T Hunter
1Molecular Biology and Virology Laboratory, Salk Institute, San Diego, California 92186.
Nature
|December 22, 1994
Resumen
La fibronectina que se une a las integrinas activa la señalización de la cinasa de adhesión focal (FAK). Esto promueve la adhesión celular y activa la vía Ras/MAPK a través de las interacciones GRB2 y c-Src.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- La cinasa de adhesión focal (FAK) es una cinasa de proteína-tirosina (PTK) del citoplasma que se localiza con los receptores de integrina en los sitios de adhesión celular.
- El compromiso de la integrina con las proteínas de la matriz extracelular como la fibronectina desencadena la fosforilación de la tirosina FAK.
Objetivo del estudio:
- Investigar el papel de FAK, GRB2 y c-Src en las vías de señalización mediadas por integrinas.
- Para dilucidar el mecanismo que vincula el compromiso de la integrina con la activación de la proteína quinasa activada por mitógeno (MAPK).
Principales métodos:
- Estudió los fibroblastos NIH3T3 que se adhieren a la fibronectina.
- Utilizó la co-inmunoprecipitación para evaluar las interacciones proteína-proteína in vivo.
- Se realizaron ensayos de unión in vitro con proteínas FAK mutadas.
Principales resultados:
- La adhesión celular inducida por fibronectina promovió la asociación de GRB2 y c-Src con FAK.
- Esta asociación fue mediada por el dominio SH2 de GRB2 que se une a FAK. fosforilado por tirosina.
- La mutación de la tirosina FAK 925 bloqueó la unión a GRB2, lo que indica su papel crítico.
- Se observó la activación de MAPK en respuesta a la estimulación de la fibronectina.
Conclusiones:
- El compromiso de la integrina con la fibronectina inicia un complejo de señalización que involucra a FAK, c-Src y GRB2.
- La fosforilación de FAK en Tyr 925 crea un sitio de unión para GRB2, vinculando la señalización de la integrina a la vía Ras/MAPK.
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