RESUMEN
Alterations to cell polarization or to intercellular junctions are often associated with epithelial cancer progression, including breast cancers (BCa). We show here that the loss of the junctional scaffold protein MAGI1 is associated with bad prognosis in luminal BCa, and promotes tumorigenesis. E-cadherin and the actin binding scaffold AMOTL2 accumulate in MAGI1 deficient cells which are subjected to increased stiffness. These alterations are associated with low YAP activity, the terminal Hippo-pathway effector, but with an elevated ROCK and p38 Stress Activated Protein Kinase activities. Blocking ROCK prevented p38 activation, suggesting that MAGI1 limits p38 activity in part through releasing actin strength. Importantly, the increased tumorigenicity of MAGI1 deficient cells is rescued in the absence of AMOTL2 or after inhibition of p38, demonstrating that MAGI1 acts as a tumor-suppressor in luminal BCa by inhibiting an AMOTL2/p38 stress pathway.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Angiomotinas/metabolismo , Neoplasias de la Mama/prevención & control , Carcinogénesis/patología , Moléculas de Adhesión Celular/metabolismo , Guanilato-Quinasas/metabolismo , Transducción de Señal , Estrés Fisiológico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Cadherinas/metabolismo , Carcinogénesis/metabolismo , Moléculas de Adhesión Celular/deficiencia , Línea Celular Tumoral , Proliferación Celular , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Guanilato-Quinasas/deficiencia , Humanos , Fenotipo , Unión Proteica , Proteínas Señalizadoras YAP/metabolismo , beta Catenina/metabolismo , Quinasas Asociadas a rho/metabolismoRESUMEN
During development, cell numbers are tightly regulated, ensuring that tissues and organs reach their correct size and shape. Recent evidence has highlighted the intricate connections between the cytoskeleton and the regulation of the key growth control Hippo pathway. Looking for apical scaffolds regulating tissue growth, we describe that Drosophila melanogaster big bang (Bbg), a poorly characterized multi-PDZ scaffold, controls epithelial tissue growth without affecting epithelial polarity and architecture. bbg-mutant tissues are smaller, with fewer cells that are less apically constricted than normal. We show that Bbg binds to and colocalizes tightly with the ß-heavy-Spectrin/Kst subunit at the apical cortex and promotes Yki activity, F-actin enrichment, and the phosphorylation of the myosin II regulatory light chain Spaghetti squash. We propose a model in which the spectrin cytoskeleton recruits Bbg to the cortex, where Bbg promotes actomyosin contractility to regulate epithelial tissue growth.