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

Fingerprint

Ligases
Ubiquitin
Breast
Stem Cells
Maintenance
Epithelial Cells
Organoids
Gene Deletion
Tamoxifen
Protein-Tyrosine Kinases
Immune System
Epithelium

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

Cite this

An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. / Mohapatra, Bhopal; Zutshi, Neha; An, Wei; Goetz, Benjamin; Arya, Priyanka; Bielecki, Timothy A.; Mustaq, Insha; Storck, Matthew D.; Meza, Jane L; Band, Vimla; Band, Hamid.

In: Journal of Cell Science, Vol. 130, No. 7, 01.04.2017, p. 1072-1086.

Research output: Contribution to journalArticle

Mohapatra, B, Zutshi, N, An, W, Goetz, B, Arya, P, Bielecki, TA, Mustaq, I, Storck, MD, Meza, JL, Band, V & Band, H 2017, 'An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance', Journal of Cell Science, vol. 130, no. 7, pp. 1072-1086. https://doi.org/10.1242/dev.138164
Mohapatra B, Zutshi N, An W, Goetz B, Arya P, Bielecki TA et al. An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. Journal of Cell Science. 2017 Apr 1;130(7):1072-1086. https://doi.org/10.1242/dev.138164
Mohapatra, Bhopal ; Zutshi, Neha ; An, Wei ; Goetz, Benjamin ; Arya, Priyanka ; Bielecki, Timothy A. ; Mustaq, Insha ; Storck, Matthew D. ; Meza, Jane L ; Band, Vimla ; Band, Hamid. / An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. In: Journal of Cell Science. 2017 ; Vol. 130, No. 7. pp. 1072-1086.
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