Dystroglycan loss disrupts polarity and beta-casein induction in mammary epithelial cells by perturbing laminin anchoring.
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.
Weir
M Lynn
ML
California Pacific Medical Center Research Institute, 475 Brannan Street, Suite 217, San Francisco, CA 94107, USA.
Oppizzi
Maria Luisa
ML
Henry
Michael D
MD
Onishi
Akiko
A
Campbell
Kevin P
KP
Bissell
Mina J
MJ
Muschler
John L
JL
D000818:Animals; D002364:Caseins / Q000378:metabolism*; D016764:Cell Polarity / Q000235:genetics*; D002478:Cells, Cultured; D002678:Chimera / Q000502:physiology; D049030:Dystroglycans / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D007797:Laminin / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D011247:Pregnancy; D017434:Protein Structure, Tertiary
D002364:Caseins; D007797:Laminin; D049030:Dystroglycans