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SIN1/MIP1 mantiene la integridad del complejo rictor-mTOR y regula la fosforilación de Akt y la especificidad del

Estela Jacinto¹, Valeria Facchinetti, Dou Liu

¹Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.

|September 12, 2006

Resumen

SIN1 es una subunidad crucial de mTORC2, esencial para la fosforilación de Akt Ser473 y la supervivencia celular. Su ausencia interrumpe la función de TORC2 pero no la de TORC1, lo que afecta a objetivos específicos de Akt como FoxO1/3a.

Área de la Ciencia:

Biología celular Biología celular.
Biología Molecular Biología Molecular
La bioquímica es la bioquímica.

Sus antecedentes:

El objetivo de la rapamicina en mamíferos (mTOR) regula el crecimiento y la proliferación celular a través de los complejos TORC1 y TORC2.
TORC2 está implicado como PDK2, fosforilando Akt/PKB en Ser473, un sitio crucial para la activación completa de Akt.
Los roles precisos de los sitios de fosforilación Akt y sus mecanismos reguladores requieren más aclaración.

Objetivo del estudio:

Para identificar las subunidades esenciales de TORC2 involucradas en la fosforilación de Akt.
Investigar el papel de SIN1/MIP1 en el contexto de la función TORC2 y la activación de Akt.
Para determinar las consecuencias fisiológicas de la fosforilación alterada de Akt Ser473 en los objetivos posteriores y la supervivencia celular.

Principales métodos:

Ablación genética del gen SIN1/MIP1 en células de mamíferos.
Análisis bioquímico de las interacciones proteína-proteína dentro de los complejos mTOR.
Evaluación de la fosforilación de Akt/PKB en Ser473 y Thr308.8.
Evaluación del estado de fosforilación de los objetivos conocidos de Akt y TORC1 (FoxO1/3a, TSC2, GSK3, S6K, 4E-BP1).

Principales resultados:

SIN1/MIP1 fue identificado como una subunidad esencial de TORC2, crítica para la interacción rictor-mTOR.
La ablación genética de SIN1 abolió la fosforilación de Akt Ser473 mientras conservaba la fosforilación de Thr308.
La fosforilación alterada de Ser473 afectó selectivamente a los objetivos de Akt como FoxO1 / 3a, dejando a los efectores TSC2, GSK3 y TORC1 (S6K, 4E-BP1) sin verse afectados.
El papel de TORC2 en la fosforilación de Akt Ser473, mediada por SIN1, es vital para la supervivencia celular.

Conclusiones:

SIN1 es indispensable para la fosforilación de Akt Ser473 mediada por TORC2.
Este evento específico de fosforilación es crucial para la función de TORC2 en la supervivencia celular.
El papel de TORC2 en la fosforilación de Akt Ser473 es distinto y prescindible para la actividad de TORC1.

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