ArticleGenes & development2011
Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation.
Article in Genes & development, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 106 papers.
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Who cites it
106 citing papers in PubMed, 187 citations in OpenAlex.
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- Extracellular matrix-driven metabolic control of pancreatic endocrine lineage allocation.EMBO reports · 2025Article
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- Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.Science (New York, N.Y.) · 2024Article
- Engineering metabolism to modulate immunity.Advanced drug delivery reviews · 2024Review
- Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.bioRxiv : the preprint server for biology · 2023Article
- Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells.iScience · 2023Article
- Identification of Basement Membrane-Related Signatures in Gastric Cancer.Diagnostics (Basel, Switzerland) · 2023Article
- Assessment of Metabolic Pathways and Parameters in Extracellular Matrix-Detached Cells.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis.Biology direct · 2022Article
- 1α,25-dihydroxyvitamin D reduction of MCF10A-ras cell viability in extracellular matrix detached conditions is dependent on regulation of pyruvate carboxylase.The Journal of nutritional biochemistry · 2022Article
- Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications.Journal of hematology & oncology · 2022Review
- Identifying platelet-derived factors as amplifiers of B. burgdorferi-induced cytokine production.Clinical and experimental immunology · 2022Article
- A practical guide for the analysis, standardization and interpretation of oxygen consumption measurements.Nature metabolism · 2022Review
- CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis.Nucleic acids research · 2022Article
- A three-organelle complex made by wrappER contacts with peroxisomes and mitochondria responds to liver lipid flux changes.Journal of cell science · 2022Article
46 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Loss of extracellular matrix (ECM) attachment leads to metabolic impairments that limit cellular energy production. Characterization of the metabolic alterations induced by ECM detachment revealed a dramatic decrease in uptake of glucose, glutamine, and pyruvate, and a consequent decrease in flux through glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle. However, flux through pyruvate dehydrogenase (PDH) is disproportionally decreased, concomitant with increased expression of the PDH inhibitory kinase, PDH kinase 4 (PDK4), and increased carbon secretion. Overexpression of ErbB2 maintains PDH flux by suppressing PDK4 expression in an Erk-dependent manner, and Erk signaling also regulates PDH flux in ECM-attached cells. Additionally, epidermal growth factor (EGF), a potent inducer of Erk, positively regulates PDH flux through decreased PDK4 expression. Furthermore, overexpression of PDK4 in ECM-detached cells suppresses the ErbB2-mediated rescue of ATP levels, and in attached cells, PDK4 overexpression decreases PDH flux, de novo lipogenesis, and cell proliferation. Mining of microarray data from human tumor data sets revealed that PDK4 mRNA is commonly down-regulated in tumors compared with their tissues of origin. These results identify a novel mechanism by which ECM attachment, growth factors, and oncogenes modulate the metabolic fate of glucose by controlling PDK4 expression and PDH flux to influence proliferation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.