mTOR generates an auto-amplification loop by triggering the βTrCP- and CK1α-dependent degradation of DEPTOR.
DEPTOR is a recently identified inhibitor of the mTOR kinase that is highly regulated at the posttranslational level. In response to mitogens, we found that DEPTOR was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the F box protein βTrCP, with consequent proteasomal degradation of DEPTOR. Phosphorylation of the βTrCP degron in DEPTOR is executed by CK1α after a priming phosphorylation event mediated by either the mTORC1 or mTORC2 complexes. Blocking the βTrCP-dependent degradation of DEPTOR via βTrCP knockdown or expression of a stable DEPTOR mutant that is unable to bind βTrCP results in mTOR inhibition. Our findings reveal that mTOR cooperates with CK1α and βTrCP to generate an auto-amplification loop to promote its own full activation. Moreover, our results suggest that pharmacologic inhibition of CK1 may be a viable therapeutic option for the treatment of cancers characterized by activation of mTOR-signaling pathways.
Department of Pathology, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
Shanshan
S
Duan
Jeffrey R
JR
Skaar
Shafi
S
Kuchay
Alfredo
A
Toschi
Naama
N
Kanarek
Yinon
Y
Ben-Neriah
Michele
M
Pagano
D048128:Casein Kinase Ialpha / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008954:Models, Biological; D010766:Phosphorylation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C556139:DEPTOR protein, human; C546842:MTOR protein, human; D048128:Casein Kinase Ialpha; D058570:TOR Serine-Threonine Kinases