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El control directo del factor de transcripción de la cabeza de horquilla AFX por la proteína quinasa B
G J Kops1, N D de Ruiter, A M De Vries-Smits
1Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, University of Utrecht, The Netherlands.
Nature
|April 27, 1999
Resumen
La proteína quinasa B regula el factor de transcripción de la cabeza de horquilla AFX, un homólogo humano de C. elegans DAF-16. Esta vía es crucial para la señalización dependiente de PI ((3) K al núcleo.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- La señalización celular de las células.
- Genética La genética.
Sus antecedentes:
- La vía de la fosfatidilinositol-3-OH-cinasa (PI(3) K) es crítica para los procesos celulares, incluida la respuesta a la insulina.
- La proteína quinasa B (PKB), un efector clave de PI(3)K, regula la expresión génica, pero se desconocen sus objetivos directos del factor de transcripción.
- El factor de transcripción Forkhead DAF-16 en C. elegans está regulado por una vía que involucra la señalización de insulina (DAF-2) y PI(3)K (AGE-1).
Objetivo del estudio:
- Para identificar los factores de transcripción regulados por la proteína quinasa B (PKB).
- Para investigar el papel de PKB en la regulación del ortólogo humano de DAF-16, AFX.
- Para aclarar la vía de señalización que conecta PI(3) K a los factores de transcripción nuclear.
Principales métodos:
- Ensayos de fosforilación in vitro e in vivo para estudiar la actividad de PKB en AFX.
- Inhibición genética y farmacológica de PI(3) K y PKB.
- Análisis de la señalización Ras y la participación de la Ral GTPasa en la fosforilación de AFX.
Principales resultados:
- La proteína quinasa B fosforila directamente el factor de transcripción Forkhead humano AFX, tanto in vitro como in vivo.
- La inhibición de PI(3)K y PKB bloquea la fosforilación AFX dependiente de PKB.
- La fosforilación residual de AFX ocurre independientemente de PKB y requiere la señalización Ras a través de Ral GTPase.
- La fosforilación de AFX por PKB inhibe su actividad transcripcional.
Conclusiones:
- Este estudio identifica a AFX como un objetivo directo de PKB, vinculando la señalización PI(3)K a la regulación de un factor de transcripción clave.
- Los hallazgos revelan un mecanismo conservado de señalización dependiente de PI ((3) K al núcleo, que implica la fosforilación de los factores de transcripción Forkhead.
- Se destaca la interacción entre las vías de señalización PKB y Ras en la regulación de la actividad AFX.
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