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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
La fosfatasa lipídica SHIP2 controla la sensibilidad a la insulina
S Clément1, U Krause, F Desmedt
1IRIBHN, IBMM, rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium.
Nature
|May 9, 2001
Resumen
SHIP2 regula negativamente la señalización de la insulina. Los ratones que carecen de SHIP2 presentan hipoglucemia severa y muerte perinatal, mientras que los ratones heterocigotos muestran una mayor sensibilidad a la insulina y tolerancia a la glucosa.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Endocrinología Endocrinología.
- Biología Molecular Biología Molecular
Sus antecedentes:
- La insulina es crucial para la homeostasis de la glucosa; su acción o secreción alterada contribuye a la diabetes mellitus.
- La inositol 5-fosfatasa (SHIP2) tipo II del dominio SH2 está implicada en el factor de crecimiento y en las vías de señalización de la insulina.
- SHIP2 interactúa con la fosfoinositida-3-OH quinasa y las vías de la proteína quinasa activada por Ras/mitógeno.
Objetivo del estudio:
- Para investigar el papel in vivo de SHIP2 en la señalización de la insulina y la homeostasis de la glucosa.
- Para caracterizar las consecuencias fisiológicas de la deleción del gen SHIP2.
Principales métodos:
- Generación y análisis de ratones que carecen del gen SHIP2.
- Evaluación de la sensibilidad a la insulina, la tolerancia a la glucosa y la expresión génica.
- Evaluación del reclutamiento del transportador GLUT4 y la síntesis de glucógeno.
Principales resultados:
- La pérdida completa de SHIP2 resultó en hipoglucemia neonatal severa, desregulación de la expresión génica de la gluconeogénesis y letalidad perinatal.
- Los ratones adultos heterocigotos mutantes SHIP2 mostraron una mejor tolerancia a la glucosa y sensibilidad a la insulina.
- El aumento de la sensibilidad a la insulina en los heterocigotos se relacionó con el aumento del reclutamiento del transportador GLUT4 y la síntesis de glucógeno en los músculos esqueléticos.
Conclusiones:
- SHIP2 actúa como un potente regulador negativo de la señalización de la insulina y la sensibilidad a la insulina in vivo.
- La modulación de la actividad de SHIP2 podría ser una estrategia terapéutica para trastornos metabólicos como la diabetes.
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