Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P42345 (
mTOR
)
26,049
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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 tamoxifen-inducible
Cbl
and
Cbl-b
deletion model with a dual fluorescent reporter (
Cbl
flox/flox
; Cbl-b
flox/flox
; Rosa26-CreERT; mT/mG
), we show that
Cbl/Cbl-b
DKO in 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.
...
PMID:An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. 3038 96
