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ErbB2 se asemeja a un autoinhibido de los invertebrados receptor del factor de crecimiento epidérmico
Diego Alvarado1, Daryl E Klein, Mark A Lemmon
1Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA.
Nature
|September 1, 2009
Resumen
La tirosina quinasa del receptor huérfano ErbB2 (HER2) puede estar regulada por ligandos, similares al EGFR de Drosophila melanogaster (dEGFR). Este hallazgo desafía la noción de que ErbB2 carece de autoinhibición y ofrece nuevas dianas terapéuticas para el cáncer.
Área de la Ciencia:
- Biología molecular La biología molecular.
- Biología estructural Biología estructural.
- Investigación de la investigación del cáncer.
Sus antecedentes:
- ErbB2 (HER2) es un receptor oncogénico tirosina quinasa y un objetivo terapéutico clave en el cáncer.
- Los modelos anteriores sugirieron que la señalización oncogénica de ErbB2 se deriva de la falta de una unión autoinhibidora presente en otros receptores ErbB.
- La base estructural de la señalización y la regulación únicas de ErbB2 sigue sin estar clara.
Objetivo del estudio:
- Investigar los mecanismos estructurales y regulatorios de la señalización ErbB2.
- Para comparar la regulación de ErbB2 con su pariente estructural más cercano, Drosophila melanogaster EGFR (dEGFR).
- Reevaluar el modelo de autoinhibición para ErbB2.
Principales métodos:
- Análisis estructural comparativo de ErbB2 y dEGFR.
- Ensayos genéticos y bioquímicos para estudiar la regulación del dEGFR por los ligandos.
- Determinación de la estructura cristalina de dEGFR.
Principales resultados:
- dEGFR, a pesar de carecer del lazo canónico, está fuertemente regulado por los ligandos del factor de crecimiento.
- Un conjunto distinto de interacciones interdominianas mantiene el dEGFR no ligado en un estado inactivo.
- Estas interacciones autoinhibidoras se conservan y se extienden en ErbB2, lo que contradice la ausencia de autoinhibición.
Conclusiones:
- La autoinhibición de ErbB2 está presente y probablemente regulada por ligandos, similares al dEGFR.
- Se desafía el modelo establecido de ErbB2 que carece de autoinhibición.
- Los hallazgos proporcionan nuevos conocimientos sobre la regulación de ErbB2 y posibles estrategias terapéuticas para los cánceres impulsados por ErbB2.
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