No abstract

Summary Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme catalyzing conversion of phosphoenolpyruvate (PEP) to pyruvate with transferring a phosphate from PEP to ADP. We report here that PKM2 localizes to the cell nucleus. The levels of nuclear PKM2 correlate with cell proliferation. PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as phosphate donor. ADP competes with the protein substrate binding, indicating that the substrate may bind to the ADP site of PKM2. Our experiments suggest that PKM2 dimer is an active protein kinase, while the tetramer is an active pyruvate kinase. Expression a PKM2 mutant that exists as a dimer promotes cell proliferation, indicating that protein kinase activity of PKM2 plays a role in promoting cell proliferation. Our study reveals an important link between metabolism alteration and gene expression during tumor transformation and progression.

Soil microbiota play a critical role in soil biogeochemical processes and have a profound effect on soil functions. Recent studies have revealed microbial co-occurrence patterns in soil microbial communities, yet the geographic pattern of topological features in soil microbial co-occurrence networks at the continental scale are largely unknown. Here, we investigated the shifts of topological features in co-occurrence networks inferred from soil microbiota along a continental scale in eastern China. Integrating archaeal, bacterial and fungal community datasets, we inferred a meta-community co-occurrence network and analyzed node-level and network-level topological shifts associated with five climatic regions. Both node-level and network-level topological features revealed geographic patterns wherein microorganisms in the northern regions had closer relationships but had a lower interaction influence than those in the southern regions. We further identified topological differences associated with taxonomic groups and demonstrated that co-occurrence patterns were random for archaea and non-random for bacteria and fungi. Given that microbial interactions may contribute to soil functions more than species diversity, this geographic shift of topological features provides new insight into studying microbial biogeographic patterns, their organization and impacts on soil-associated function.

D-type cyclins (D1, D2 and D3) together with their associated cyclin-dependent kinases CDK4 and CDK6 are components of the core cell cycle machinery that drives cell proliferation1,2. Inhibitors of CDK4 and CDK6 are currently in clinical trials for patients with several cancer types, with promising results2. Here, we show that cyclin D3-CDK6 phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. This re-directs the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumor cells reduces PPP and serine pathway flows, thereby depleting anti-oxidants NADPH and glutathione. This, in turn elevates the levels of reactive oxygen species and causes tumor cell apoptosis. The pro-survival function of cyclin D-associated kinase operates in tumors expressing high levels of cyclin D3-CDK6 complexes. We propose that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumor subsets that undergo cell death and tumor regression upon CDK4/6-inhibition. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism represents a particularly powerful oncogene that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy.