Abstract
The insulin receptor gene encodes an evolutionarily conserved signaling protein with a wide spectrum of functions in metazoan development. The insulin signaling pathway plays key roles in processes such as metabolic regulation, growth control, and neuronal function. Misregulation of the pathway features in diabetes, cancer, and neurodegenerative diseases, making it an important target for clinical interventions. While much attention has been focused on differential pathway activation through ligand availability, sensitization of overall signaling may also be mediated by differential expression of the insulin receptor itself. Although first characterized as a “housekeeping” gene with stable expression, comparative studies have shown that expression levels of the human INSR mRNA differ by tissue and in response to environmental signals. Our recent analysis of the transcriptional controls affecting expression of the Drosophila insulin receptor gene indicates that a remarkable amount of DNA is dedicated to encoding sophisticated feedback and feed forward signals. The human INSR gene is likely to contain a similar level of transcriptional complexity; here, we summarize over three decades of molecular biology and genetic research that points to a still incompletely understood regulatory control system. Further elucidation of transcriptional controls of INSR will provide the basis for understanding human genetic variation that underlies population-level physiological differences and disease.
Highlights
The insulin receptor gene encodes an evolutionarily conserved signaling protein with a wide spectrum of functions in metazoan development
DFOXO-deficient flies under similar conditions showed no change in the Insulin-like Receptor protein (InR) expression level, suggesting dFOXO is directly involved in the response to nutrients [5]
To gain a better insight into the likely relevant control regions, we summarize below our understanding of the insulin receptor chromatin landscape of INSR and sequences associated with population-level variation and disease
Summary
The insulin signaling pathway in metazoans regulates diverse processes including cell growth and metabolic homeostasis. The active sites of the beta subunits come into close contact with each other and trans-phosphorylate neighboring tyrosine residues These phosphorylated tyrosine residues serve as binding sites for adaptor proteins involved in transducing the signal through the cell. Auto-phosphorylation first allows for the binding of adaptor proteins, including insulin receptor substrate 1 (IRS1) to the intracellular phosphorylated tyrosine residues, leading to phosphorylation of this signal mediator. IR activation can lead to a signaling cascade involving the MAPK signaling pathway, which leads to the activation of mTOR and other transcription factors [6] These insulin receptor-mediated signaling pathways are highly conserved across metazoans, with homologs to IR, IRS-1, PI3K, FOXO, and other proteins found in C. elegans, mouse, and Drosophila [7]. The significance of transcriptional regulation for this gene is only starting to come into view, and this review will summarize convergent lines of evidence that lend urgency to deciphering this important but little-explored level of regulation for the key receptor of an ancient metazoan pathway
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