Amino Acid Activation of mTORC1 by a PB1-Domain-Driven Kinase Complex Cascade.
The mTORC1 complex is central to the cellular response to changes in nutrient availability. The signaling adaptor p62 contributes to mTORC1 activation in response to amino acids and interacts with TRAF6, which is required for the translocation of mTORC1 to the lysosome and the subsequent K63 polyubiquitination and activation of mTOR. However, the signal initiating these p62-driven processes was previously unknown. Here, we show that p62 is phosphorylated via a cascade that includes MEK3/6 and p38δ and is driven by the PB1-containing kinase MEKK3. This phosphorylation results in the recruitment of TRAF6 to p62, the ubiquitination and activation of mTOR, and the regulation of autophagy and cell proliferation. Genetic inactivation of MEKK3 or p38δ mimics that of p62 in that it leads to inhibited growth of PTEN-deficient prostate organoids. Analysis of human prostate cancer samples showed upregulation of these three components of the pathway, which correlated with enhanced mTORC1 activation.
Cell Death and Survival Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Juan F
JF
Linares
Cell Death and Survival Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Angeles
A
Duran
Cell Death and Survival Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Miguel
M
Reina-Campos
Functional Genomics Core, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Pedro
P
Aza-Blanc
Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Alex
A
Campos
Cell Death and Survival Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Jorge
J
Moscat
Cell Death and Survival Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: mdmeco@sbpdiscovery.org.
Maria T
MT
Diaz-Meco
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D021381:Protein Transport; D000071456:Sequestosome-1 Protein; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D006360:Heat-Shock Proteins; D046912:Multiprotein Complexes; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048748:MAP Kinase Kinase Kinase 3; C482626:Map3k3 protein, mouse; D051059:PTEN Phosphohydrolase