mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR.
The activities of both mTORC1 and mTORC2 are negatively regulated by their endogenous inhibitor, DEPTOR. As such, the abundance of DEPTOR is a critical determinant in the activity status of the mTOR network. DEPTOR stability is governed by the 26S-proteasome through a largely unknown mechanism. Here we describe an mTOR-dependent phosphorylation-driven pathway for DEPTOR destruction via SCF(βTrCP). DEPTOR phosphorylation by mTOR in response to growth signals, and in collaboration with casein kinase I (CKI), generates a phosphodegron that binds βTrCP. Failure to degrade DEPTOR through either degron mutation or βTrCP depletion leads to reduced mTOR activity, reduced S6 kinase activity, and activation of autophagy to reduce cell growth. This work expands the current understanding of mTOR regulation by revealing a positive feedback loop involving mTOR and CKI-dependent turnover of its inhibitor, DEPTOR, suggesting that misregulation of the DEPTOR destruction pathway might contribute to aberrant activation of mTOR in disease.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Daming
D
Gao
Hiroyuki
H
Inuzuka
Meng-Kwang Marcus
MK
Tan
Hidefumi
H
Fukushima
Jason W
JW
Locasale
Pengda
P
Liu
Lixin
L
Wan
Bo
B
Zhai
Y Rebecca
YR
Chin
Shavali
S
Shaik
Costas A
CA
Lyssiotis
Steven P
SP
Gygi
Alex
A
Toker
Lewis C
LC
Cantley
John M
JM
Asara
J Wade
JW
Harper
Wenyi
W
Wei
D001343:Autophagy; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D010766:Phosphorylation; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014162:Transfection
D047908:Intracellular Signaling Peptides and Proteins; D044843:SKP Cullin F-Box Protein Ligases; C556139:DEPTOR protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases