The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C.
The target of rapamycin (TOR), as part of the rapamycin-sensitive TOR complex 1 (TORC1), regulates various aspects of protein synthesis. Whether TOR functions in this process as part of TORC2 remains to be elucidated. Here, we demonstrate that mTOR, SIN1 and rictor, components of mammalian (m)TORC2, are required for phosphorylation of Akt and conventional protein kinase C (PKC) at the turn motif (TM) site. This TORC2 function is growth factor independent and conserved from yeast to mammals. TM site phosphorylation facilitates carboxyl-terminal folding and stabilizes newly synthesized Akt and PKC by interacting with conserved basic residues in the kinase domain. Without TM site phosphorylation, Akt becomes protected by the molecular chaperone Hsp90 from ubiquitination-mediated proteasome degradation. Finally, we demonstrate that mTORC2 independently controls the Akt TM and HM sites in vivo and can directly phosphorylate both sites in vitro. Our studies uncover a novel function of the TOR pathway in regulating protein folding and stability, processes that are most likely linked to the functions of TOR in protein synthesis.
Department of Immunology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA. vfacchin@mdanderson.org
Valeria
V
Facchinetti
Weiming
W
Ouyang
Hua
H
Wei
Nelyn
N
Soto
Adam
A
Lazorchak
Christine
C
Gould
Carolyn
C
Lowry
Alexandra C
AC
Newton
Yuxin
Y
Mao
Robert Q
RQ
Miao
William C
WC
Sessa
Jun
J
Qin
Pumin
P
Zhang
Bing
B
Su
Estela
E
Jacinto
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000378:metabolism; D017510:Protein Folding; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C