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Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
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Un conmutador de miristoil/fosfotirosina regula el c-Ablbl
Oliver Hantschel1, Bhushan Nagar, Sebastian Guettler
1Developmental Biology Programme, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
Cell
|March 26, 2003
Resumen
La c-Abl tirosina quinasa utiliza un interruptor de miristoil/fosfotirosina para su activación, a diferencia de las Src quinasas. Este interruptor explica la activación de c-Abl y la sensibilidad al fármaco para la leucemia STI-571.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Oncología Oncología.
Sus antecedentes:
- La c-Abl tirosina quinasa juega un papel crucial en la señalización celular, y su desregulación en la oncoproteína Bcr-Abl está implicada en la leucemia humana.
- Comprender los mecanismos precisos de la inhibición de c-Abl es esencial para desarrollar terapias efectivas contra el cáncer.
Objetivo del estudio:
- Para dilucidar el mecanismo de activación de la c-Abl tirosina quinasa.
- Para investigar el papel de la modificación N-terminal de miristoil en la regulación de c-Abl.
- Proporcionar información sobre el mecanismo de acción del medicamento contra el cáncer STI-571 (imatinib).
Principales métodos:
- Análisis comparativo de los mecanismos de activación de c-Abl y Src kinasa.
- Estudios funcionales que involucran la unión de ligandos y las interacciones de proteínas.
- Análisis estructural para definir las interacciones moleculares.
- Investigando el efecto de STI-571 en el c-Abl. activado por ligando.
Principales resultados:
- c-Abl 1b es activado por ligandos de fosfotirosina, similares a las Src quinasas.
- La modificación N-terminal de myristoyl de c-Abl involucra el dominio de la quinasa, reemplazando la interacción cola fosforilada del dominio Src SH2.
- Un interruptor de miristoil/fosfotirosina en c-Abl regula el acoplamiento y la accesibilidad del dominio SH2.
- El c-Abl activado por ligando demuestra una mayor sensibilidad a la STI-571.
Conclusiones:
- El interruptor de miristoil/fosfotirosina proporciona un nuevo mecanismo para la activación de c-Abl por las proteínas fosforiladas por tirosina.
- Este interruptor explica la movilidad intracelular de c-Abl y su sensibilidad a STI-571.1.
- Los hallazgos ofrecen nuevas perspectivas sobre la acción terapéutica de STI-571 en leucemias asociadas con Bcr-Abl.
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