Abstract

The ubiquitin ligases CBL and CBL-B are negative regulators of tyrosine kinase signaling with established roles in the immune system. However, their physiological roles in epithelial tissues are unknown. Here, we used MMTV-Cre-mediated Cbl gene deletion on a Cbl-b null background, as well as a tamoxifen-inducible mammary stem cell (MaSC)-specific Cbl and Cbl-b double knockout (Cbl/Cbl-b DKO) using Lgr5-EGFP-IRES-CreERT2, to demonstrate a mammary epithelial cell-autonomous requirement of CBL and CBL-B in the maintenance of MaSCs. Using a newly engineered tamoxifeninducible Cbl and Cbl-b deletion model with a dual fluorescent reporter (Cblflox/flox; Cbl-bflox/flox; Rosa26-CreERT; mT/mG), we show that Cbl/Cbl-b DKOin mammary organoids leads to hyperactivation of AKT-mTOR signaling with depletion of MaSCs. Chemical inhibition of AKT or mTOR rescued MaSCs from Cbl/Cbl-b DKO-induced depletion. Our studies reveal a novel, cell-autonomous requirement of CBL and CBL-B in epithelial stem cell maintenance during organ development and remodeling through modulation of mTOR signaling.

Original languageEnglish (US)
Pages (from-to)1072-1086
Number of pages15
JournalJournal of Cell Science
Volume130
Issue number7
DOIs
StatePublished - Apr 1 2017

Keywords

  • Basal cells
  • Casitas B-lineage lymphoma
  • CBLB
  • Lgr5
  • Luminal cells
  • Mammary gland development
  • Mammary stem cells
  • Mouse
  • MTOR signaling

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Mohapatra, B., Zutshi, N., An, W., Goetz, B., Arya, P., Bielecki, T. A., Mustaq, I., Storck, M. D., Meza, J. L., Band, V., & Band, H. (2017). An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. Journal of Cell Science, 130(7), 1072-1086. https://doi.org/10.1242/dev.138164