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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

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Activación dependiente de la quinasa 1-dependiente de la ciclina de la ubiquitina ligasa APC/C

Kazuyuki Fujimitsu¹, Margaret Grimaldi¹, Hiroyuki Yamano²

¹Cell Cycle Control Group, UCL Cancer Institute, University College London, London WC1E 6DD, UK.

Science (New York, N.Y.)

|April 23, 2016

Resumen

El complejo promotor de anafase/ciclosoma (APC/C) controla la división celular. Los investigadores descubrieron cómo la fosforilación CDK1 de las subunidades APC/C la activa, revelando un nuevo mecanismo para regular la progresión del ciclo celular.

Área de la Ciencia:

Biología celular
Biología molecular
La bioquímica

Sus antecedentes:

El complejo promotor de anafase o ciclosoma (APC / C) es una ligasa ubiquitina E3 crucial para la duplicación y segregación precisa del genoma durante la división celular.
La actividad de APC/C está estrictamente regulada por la fosforilación, pero los mecanismos precisos siguen siendo incompletamente entendidos.

Objetivo del estudio:

Elucidar el mecanismo por el cual la cinasa dependiente de ciclina 1 (CDK1) fosforila y activa el APC/C.
Identificar las subunidades APC/C específicas involucradas en la activación mediada por CDK1 y comprender las consecuencias funcionales.

Principales métodos:

Reconstitución sistemática de APC/C de vertebrados bajo condiciones fisiológicas.
Análisis bioquímico de la fosforilación APC/C por CDK1 en complejo con p9/Cks2.
Mutagenesis dirigida al sitio, incluidas las mutaciones fosfomiméticas, para evaluar el impacto funcional.

Principales resultados:

La fosforilación mediada por CDK1 de las subunidades Apc3 y Apc1 es crítica para la activación de APC/C.
La fosforilación de los dominios del bucle por CDK1/p9/Cks2 controla la carga del coactivador Cdc20 en el APC/C.
Una mutación fosfomimética en Apc1 permitió a Cdc20 aumentar la actividad de APC/C durante la interfase, lo que demuestra la comunicación entre subunidades.

Conclusiones:

Se ha definido un nuevo mecanismo de comunicación subunidad-subunidad de largo alcance dentro de la APC/C activado por la fosforilación de CDK1.
Estos hallazgos aclaran el papel funcional de la fosforilación de CDK en la regulación de la actividad APC/C y la progresión del ciclo celular.
Cdc20 emerge como un objetivo terapéutico potencial para el desarrollo de nuevos inhibidores para enfermedades que implican desregulación del ciclo celular.

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