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P-Rex1, a PtdIns(3,4,5) P3- y el factor de intercambio de guanina-nucleótido regulado por Gbetagamma para Rac
Heidi C E Welch1, W John Coadwell, Christian D Ellson
1Inositide Laboratory, Cambridge CB2 4AT, United Kingdom.
Cell
|April 17, 2002
Resumen
Los investigadores identificaron P-Rex1, un nuevo activador de Rac, crucial para la señalización de los neutrófilos. Este factor de intercambio guanina-nucleótido (GEF) es activado por lípidos específicos y subunidades de proteína G, lo que afecta las respuestas celulares.
Área de la Ciencia:
- Biología celular Biología celular.
- La señalización molecular.
- Inmunología Inmunología.
Sus antecedentes:
- Las Rac GTPasas son reguladores clave de los procesos celulares.
- La señalización de los neutrófilos implica complejas vías intracelulares.
- Los fosfoinosítidos y las proteínas G juegan un papel crítico en la activación celular.
Objetivo del estudio:
- Identificar y caracterizar nuevos activadores de Rac en los neutrófilos.
- Para aclarar los mecanismos reguladores de la activación de Rac.
- Comprender el papel de la señalización Rac en la función de los neutrófilos.
Principales métodos:
- Purificación de un activador Rac PtdIns ((3,4,5) P3-sensible a partir del citosol de los neutrófilos.
- La clonación y la expresión recombinante de la proteína identificada, P-Rex1.
- Ensayos in vitro e in vivo para evaluar la actividad del factor de intercambio guanina-nucleótido (GEF) de P-Rex1.
- Uso de oligonucleótidos antisense para evaluar la función de P-Rex1 en células similares a los neutrófilos.
Principales resultados:
- Un nuevo GEF de 185 kDa, llamado P-Rex1, fue purificado e identificado como un activador de Rac.
- La actividad de P-Rex1 es directamente, sustancialmente y sinérgicamente activada por el fosfatidilinositol (3,4,5)-trisfosfato (PtdIns(3,4,5) P3) y las subunidades de Gbetagamma.
- La regulación a la baja de P-Rex1 utilizando oligonucleótidos antisense redujo la formación de especies reactivas de oxígeno en respuesta a la estimulación C5a.
- P-Rex1 funciona como un detector de coincidencias para las vías de señalización PtdIns{3,4,5) P3 y Gbetagamma.
Conclusiones:
- P-Rex1 es un nuevo y crítico factor de intercambio de guanina y nucleótido Rac en los neutrófilos.
- P-Rex1 integra las señales de las vías PtdIns{3,4,5) P3 y Gbetagamma.
- P-Rex1 juega un papel importante en la activación de los neutrófilos, particularmente en respuesta a los quimioatractores como C5a.
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