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

Nat Commun. 2021 May 19;12(1):2939. doi: 10.1038/s41467-021-23269-8.


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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Substitution
  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Cell Movement / genetics
  • Female
  • Gene Knock-In Techniques
  • Humans
  • Mammary Glands, Animal / growth & development*
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Human / growth & development*
  • Mammary Glands, Human / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • Morphogenesis
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Organoids / growth & development
  • Organoids / metabolism
  • Phosphorylation
  • Protein Biosynthesis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Serine / chemistry
  • bcl-Associated Death Protein / deficiency
  • bcl-Associated Death Protein / genetics
  • bcl-Associated Death Protein / metabolism*


  • Adaptor Proteins, Signal Transducing
  • BAD protein, human
  • Bad protein, mouse
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Eif4ebp1 protein, mouse
  • Mutant Proteins
  • RNA, Messenger
  • bcl-Associated Death Protein
  • Serine