Research ArticleCancer

Phosphorylation of eIF2α triggered by mTORC1 inhibition and PP6C activation is required for autophagy and is aberrant in PP6C-mutated melanoma

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Science Signaling  10 Mar 2015:
Vol. 8, Issue 367, pp. ra27
DOI: 10.1126/scisignal.aaa0899

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Linking kinases in autophagy initiation

Cells initiate autophagy to reclaim nutrients under starvation conditions. One stimulus for autophagy is amino acid deprivation, which inhibits one kinase (mTOR) and activates another (GCN2). Wengrod et al. found that inhibition of mTOR stimulated the phosphatase PP6C, resulting in the activation of GCN2, which promoted the phosphorylation of eIF2α, a protein translation factor, and autophagy. Cells expressing forms of PP6C with certain melanoma-associated mutations and human melanoma samples genotyped for these mutations showed increased phosphorylation of eIF2α and autophagy.