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BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models

Elucidation of non-canonical protein functions can identify novel tissue homeostasis pathways. Herein, we describe a role for the Bcl-2 family member BAD in postnatal mammary gland morphogenesis. In Bad(3SA) knock-in mice, where BAD cannot undergo phosphorylation at 3 key serine residues, pubertal g...

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Detalles Bibliográficos
Autores principales: Githaka, John Maringa, Tripathi, Namita, Kirschenman, Raven, Patel, Namrata, Pandya, Vrajesh, Kramer, David A., Montpetit, Rachel, Zhu, Lin Fu, Sonenberg, Nahum, Fahlman, Richard P., Danial, Nika N., Underhill, D. Alan, Goping, Ing Swie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134504/
https://www.ncbi.nlm.nih.gov/pubmed/34011960
http://dx.doi.org/10.1038/s41467-021-23269-8
Descripción
Sumario:Elucidation of non-canonical protein functions can identify novel tissue homeostasis pathways. Herein, we describe a role for the Bcl-2 family member BAD in postnatal mammary gland morphogenesis. In Bad(3SA) knock-in mice, where BAD cannot undergo phosphorylation at 3 key serine residues, pubertal gland development is delayed due to aberrant tubulogenesis of the ductal epithelium. Proteomic and RPPA analyses identify that BAD regulates focal adhesions and the mRNA translation repressor, 4E-BP1. These results suggest that BAD modulates localized translation that drives focal adhesion maturation and cell motility. Consistent with this, cells within Bad(3SA) organoids contain unstable protrusions with decreased compartmentalized mRNA translation and focal adhesions, and exhibit reduced cell migration and tubulogenesis. Critically, protrusion stability is rescued by 4E-BP1 depletion. Together our results confirm an unexpected role of BAD in controlling localized translation and cell migration during mammary gland development.