Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma.

08:00 EDT 16th March 2020 | BioPortfolio

Summary of "Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma."

Although the transition metal copper (Cu) is an essential nutrient that is conventionally viewed as a static cofactor within enzyme active sites, a non-traditional role for Cu as a modulator of kinase signalling is emerging. Here, we found that Cu is required for the activity of the autophagic kinases ULK1 and ULK2 (ULK1/2) through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt the binding of Cu reduced ULK1/2-dependent signalling and the formation of autophagosome complexes. Increased levels of intracellular Cu are associated with starvation-induced autophagy and are sufficient to enhance ULK1 kinase activity and, in turn, autophagic flux. The growth and survival of lung tumours driven by KRAS is diminished in the absence of Ctr1, is dependent on ULK1 Cu binding and is associated with reduced levels of autophagy and signalling. These findings suggest a molecular basis for exploiting Cu-chelation therapy to prevent autophagy signalling to limit proliferation and improve patient survival in cancer.


Journal Details

This article was published in the following journal.

Name: Nature cell biology
ISSN: 1476-4679


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Medical and Biotech [MESH] Definitions

P-type ATPases which transport copper ions across membranes in prokaryotic and eukaryotic cells. They possess a conserved CYSTEINE-HISTIDINE-SERINE (CPx) amino acid motif within their transmembrane helices that functions in cation translocation and catalytic activation, and an N-terminal copper-binding CxxC motif that regulates enzyme activity. They play essential roles in intracellular copper homeostasis through regulating the uptake, efflux and storage of copper ions, and in cuproprotein biosynthesis.

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Unstable isotopes of copper that decay or disintegrate emitting radiation. Cu atoms with atomic weights 58-62, 64, and 66-68 are radioactive copper isotopes.

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