Abstract
AbstractElucidation 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 Bad3SA 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 Bad3SA 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.
Funder
Alberta Cancer Foundation
Gouvernement du Canada | Canadian Institutes of Health Research
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference104 articles.
1. Yang, E. et al. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80, 285–291 (1995).
2. Gilmore, A. P. et al. Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. J. Biol. Chem. 277, 27643–27650 (2002).
3. Kitada, S. et al. Expression and location of pro-apoptotic Bcl-2 family protein BAD in normal human tissues and tumor cell lines. Am. J. Pathol. 152, 51–61 (1998).
4. Zha, J. et al. BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity. J. Biol. Chem. 272, 24101–24104 (1997).
5. Danial, N. N. BAD: undertaker by night, candyman by day. Oncogene 27, 53 (2008).
Cited by
4 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献