Abstract
The insulin/IGF-activated AKT signaling pathway plays a crucial role in regulating tissue growth and metabolism in multicellular animals. Although core components of the pathway are well defined, less is known about mechanisms that adjust the sensitivity of the pathway to extracellular stimuli. In humans, disturbance in insulin sensitivity leads to impaired clearance of glucose from the blood stream, which is a hallmark of diabetes. Here we present the results of a genetic screen in Drosophila designed to identify regulators of insulin sensitivity in vivo. Components of the MAPK/ERK pathway were identified as modifiers of cellular insulin responsiveness. Insulin resistance was due to downregulation of insulin-like receptor gene expression following persistent MAPK/ERK inhibition. The MAPK/ERK pathway acts via the ETS-1 transcription factor Pointed. This mechanism permits physiological adjustment of insulin sensitivity and subsequent maintenance of circulating glucose at appropriate levels.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Culture Techniques
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DNA-Binding Proteins / metabolism*
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / genetics*
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Drosophila melanogaster / metabolism
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ErbB Receptors / metabolism
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation
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Glucose / metabolism*
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Insulin / genetics
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Insulin / metabolism*
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Insulin Resistance / genetics*
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Nerve Tissue Proteins / metabolism*
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Protein Kinases / metabolism
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Proto-Oncogene Protein c-ets-1 / metabolism
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Proto-Oncogene Proteins / metabolism*
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Signal Transduction / genetics
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Transcription Factors / metabolism*
Substances
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DNA-Binding Proteins
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Drosophila Proteins
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FOXO protein, Drosophila
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Forkhead Transcription Factors
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Insulin
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Nerve Tissue Proteins
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins
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Transcription Factors
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pnt protein, Drosophila
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Protein Kinases
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KSR-1 protein kinase
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ErbB Receptors
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InR protein, Drosophila
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Receptor Protein-Tyrosine Kinases
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Mitogen-Activated Protein Kinase Kinases
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Glucose