PP2A T61 epsilon is an inhibitor of MAP4K3 in nutrient signaling to mTOR.
The mammalian target of rapamycin (mTOR) pathway is activated by a variety of stimuli, including nutrients such as glucose and amino acids. The Ste20 family kinase MAP4K3 is regulated by amino acids and acts upstream of mTORC1. Here we investigate how MAP4K3 activity is regulated by amino acid sufficiency. We identify a transautophosphorylation site in the MAP4K3 kinase activation segment (Ser170) that is required for MAP4K3 activity and its activation of mTORC1 signaling. Following amino acid withdrawal, Ser170 is dephosphorylated via PP2A complexed to PR61 epsilon, a PP2A-targeting subunit. Inhibition of PR61 epsilon expression prevents MAP4K3 Ser170 dephosphorylation and impairs mTORC1 inhibition during amino acid withdrawal. We propose that during amino acid sufficiency Ser170-phosphorylated MAP4K3 activates mTORC1, but that upon amino acid restriction MAP4K3 preferentially interacts with PP2A(T61 epsilon), promoting dephosphorylation of Ser170, MAP4K3 inhibition, and, subsequently, inhibition of mTORC1 signaling.
Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, AB T6G IZ2, Canada.
Lijun
L
Yan
Virginie
V
Mieulet
Darren
D
Burgess
Greg M
GM
Findlay
Katherine
K
Sully
Julia
J
Procter
Jozef
J
Goris
Veerle
V
Janssens
Nick A
NA
Morrice
Richard F
RF
Lamb
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids / Q000172:deficiency / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D011506:Proteins / Q000378:metabolism; D034622:RNA Interference; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D047908:Intracellular Signaling Peptides and Proteins; D021122:Protein Subunits; D011506:Proteins; C463659:RPTOR protein, human; C430722:RRAGC protein, human; C430723:RRAGD protein, human; D000076223:Regulatory-Associated Protein of mTOR; C546842:MTOR protein, human; C543044:MAP4K3 protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D054648:Protein Phosphatase 2; D020559:Monomeric GTP-Binding Proteins