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La oligomerización inducida por heparina de las moléculas del FGF es responsable de la dimerización, activación y
T Spivak-Kroizman1, M A Lemmon, I Dikic
1Department of Pharmacology, New York University Medical Center, New York 10016.
Cell
|December 16, 1994
Resumen
La heparina es esencial para que el factor de crecimiento de los fibroblastos (FGF) active su receptor (FGFR). La heparina hace que el FGF se agrupe, lo que permite la dimerización del receptor y la señalización aguas abajo para el crecimiento celular.
Área de la Ciencia:
- Biología celular Biología celular.
- La bioquímica es la bioquímica.
- La señalización molecular.
Sus antecedentes:
- El factor de crecimiento de los fibroblastos (FGF) que se une a su receptor (FGFR) es crucial para las respuestas celulares.
- Se sabe que la heparina es necesaria para la señalización mediada por el FGF, pero su papel preciso no ha sido claro.
Objetivo del estudio:
- Aclarar el mecanismo por el cual la heparina facilita la señalización mediada por el FGF.
- Para investigar el papel de la heparina en la dimerización y activación del receptor FGF (FGFR).
Principales métodos:
- Se utilizó calorimetría de titulación isotérmica para estudiar la interacción entre el FGF ácido (aFGF) y el FGFR soluble.
- Se realizaron experimentos en líneas celulares que carecían de sulfato de heparano endógeno para evaluar la necesidad de heparina exógena.
- Se utilizó un análogo sintético de heparina para investigar el papel de la unión multivalente de la heparina.
Principales resultados:
- El FGF ácido (aFGF) forma un complejo 1:1 con el dominio extracelular soluble del FGFR.
- La heparina se une a múltiples moléculas de aFGF, formando un complejo aFGF-heparina capaz de unirse a varios FGFR.
- Esta formación compleja conduce a la dimerización del FGFR, la activación de la tirosina quinasa, la transcripción del ARNm c-fos y la proliferación celular en líneas celulares deficientes.
- Un análogo de heparina monovalente inhibió la dimerización del FGFR y la señalización aguas abajo.
Conclusiones:
- La heparina induce la oligomerización de aFGF, lo que promueve la dimerización del FGFR y la subsiguiente transducción de la señal.
- Este estudio revela un nuevo mecanismo para la señalización transmembrana mediada por factores de crecimiento ligados a la heparina.
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