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. [Display omitted] •p62 is phosphorylated in response to amino acids by p38δ in a MEKK3-dependent manner•p62 phosphorylation recruits TRAF6 and promotes mTORC1 translocation to lysosomes•p38δ-mediated p62 phosphorylation is required for mTORC1 activation by amino acids•The MEKK3/p38δ kinase cascade modulates autophagy and cancer growth via mTORC1 Linares et al. identify a kinase cascade that regulates the phosphorylation of the signal adaptor p62 in response to amino acids to control mTORC1 activation. This nutrient-sensing mechanism is relevant for autophagy regulation and tumor growth.