Amino Acid Activation of mTORC1 by a PB1-Domain-Driven Kinase Complex Cascade. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • August 13, 2015

Research

keywords

  • Amino Acids
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Signaling System
  • Multiprotein Complexes
  • Prostatic Neoplasms
  • TOR Serine-Threonine Kinases

Identity

PubMed Central ID

  • PMC4551582

Scopus Document Identifier

  • 84939800232

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2015.07.045

PubMed ID

  • 26279575

Additional Document Info

volume

  • 12

issue

  • 8