An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance
Abstract
CBL and CBL-B ubiquitin ligases 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 the MMTV-Cre-mediated Cbl gene deletion on a Cbl-b-null background as well as a tamoxifen-inducible mammary stem cell (MaSC)-specific Cbl/Cbl-b double knockout (DKO), using Lgr5-GFP-CreERT, to demonstrate a mammary epithelial cell-autonomous requirement of CBL and CBL-B in the maintenance of MaSCs. Using a newly engineered tamoxifen (TAM)-inducible Cbl/Cbl-b deletion model with a dual fluorescent reporter (Cblflox/flox; Cbl-bflox/flox; Rosa26-CreERT; mT/mG), we show that Cbl/Cbl-b DKO in mammary organoids leads to hyper-activation 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2017
- Source ID
- 10.1242/dev.138164
Entities
People
- Benjamin Goetz
- Bhopal Mohapatra
- Hamid Band
- Insha Mustaq
- Jane L. Meza
- Matthew D Storck
- Neha Zutshi
- Priyanka Arya
- Timothy A. Bielecki
- Wei An
Organizations
- Office of Extramural Research
- United States Department of Defense
- University of Nebraska Medical Center
- University of Nebraska–Lincoln