RESUMEN
Precise contact between epithelial cells and their underlying basement membrane is crucial to the maintenance of tissue architecture and function. To understand the role that the laminin receptor dystroglycan (DG) plays in these processes, we assayed cell responses to laminin-111 following conditional ablation of DG gene (Dag1) expression in cultured mammary epithelial cells. Strikingly, DG loss disrupted laminin-111-induced polarity and beta-casein production, and abolished laminin assembly at the step of laminin binding to the cell surface. Dystroglycan re-expression restored these deficiencies. Investigations of the mechanism revealed that DG cytoplasmic sequences were not necessary for laminin assembly and signaling, and only when the entire mucin domain of extracellular DG was deleted did laminin assembly not occur. These results demonstrate that DG is essential as a laminin-111 co-receptor in mammary epithelial cells that functions by mediating laminin anchoring to the cell surface, a process that allows laminin polymerization, tissue polarity and beta-casein induction. The observed loss of laminin-111 assembly and signaling in Dag1(-/-) mammary epithelial cells provides insights into the signaling changes occurring in breast carcinomas and other cancers, where the binding function of DG to laminin is frequently defective.
Asunto(s)
Caseínas/metabolismo , Polaridad Celular/genética , Distroglicanos/genética , Distroglicanos/fisiología , Células Epiteliales/metabolismo , Laminina/metabolismo , Glándulas Mamarias Animales/citología , Animales , Células Cultivadas , Quimera/fisiología , Distroglicanos/química , Femenino , Ratones , Ratones Transgénicos , Modelos Biológicos , Embarazo , Estructura Terciaria de ProteínaRESUMEN
Dystroglycan (DG) is a single receptor that binds to multiple basement membrane proteins and forms a transmembrane link to the actin cytoskeleton. It was first isolated as a component of the dystrophin-glycoprotein complex, which plays a role in the maintenance of muscle cell integrity and is defective in many muscular dystrophies. Although studied most extensively in muscle tissues, DG is present at most cell-basement membrane interfaces, and only recently has investigation of DG functions in nonmuscle cells gained momentum. Information emerging from recent studies in epithelial cells is implicating DG in a wide range of critical cell responses to the basement membrane, ranging from organization of tissue architecture to cell survival. Moreover, DG functions appear to be frequently absent in carcinoma cells, implicating its loss in cancer progression. Although many questions remain as to its precise role in mammary tissue, DG is emerging as a potentially important player in mammary gland function.