Biochemical characterization of the Drosophila insulin receptor kinase and longevity‐associated mutants
1
Citation
72
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract Drosophila melanogaster (fruit fly) insulin receptor (D‐IR) is highly homologous to the human counterpart. Like the human pathway, D‐IR responds to numerous insulin‐like peptides to activate cellular signals that regulate growth, development, and lipid metabolism in fruit flies. Allelic mutations in the D‐IR kinase domain elevate life expectancy in fruit flies. We developed a robust heterologous expression system to express and purify wild‐type and longevity‐associated mutant D‐IR kinase domains to investigate enzyme kinetics and substrate specificities. D‐IR exhibits remarkable similarities to the human insulin receptor kinase domain but diverges in substrate preferences. We show that longevity‐associated mutations reduce D‐IR catalytic activity. Deletion of the unique kinase insert domain portion or mutations proximal to activating tyrosines do not influence kinase activity, suggesting their potential role in substrate recruitment and downstream signaling. Through biochemical investigations, this study enhances our comprehension of D‐IR's role in Drosophila physiology, complementing genetic studies and expanding our knowledge on the catalytic functions of this conserved signaling pathway.Keywords:
Protein kinase domain
Model Organism
Insulin/insulin-like growth factor (IGF)-1 signaling (IIS) pathway regulates aging in many organisms, ranging from simple invertebrates to mammals, including humans. Many seminal discoveries regarding the roles of IIS in aging and longevity have been made by using the roundworm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. In this review, we describe the mechanisms by which various IIS components regulate aging in C. elegans and D. melanogaster. We also cover systemic and tissue-specific effects of the IIS components on the regulation of lifespan. We further discuss IIS-mediated physiological processes other than aging and their effects on human disease models focusing on C. elegans studies. As both C. elegans and D. melanogaster have been essential for key findings regarding the effects of IIS on organismal aging in general, these invertebrate models will continue to serve as workhorses to help our understanding of mammalian aging.
Melanogaster
Model Organism
Cite
Citations (176)
Traditionally, ageing has been considered a passive and entropic process, in which damages accumulate on biological macromolecules over time and the accumulated damages lead to a decline in overall physiological functions. However, the discovery of a longevity mutant in the nematode Caenorhabditis elegans has challenged this view. A longevity mutant is a mutant organism, in which a reduction-of-function of a certain gene prolongs the lifespan. Thus, the discovery of longevity mutants has shown the existence of genes, which function to shorten lifespan in wild-type organisms, promoting extensive hunting for longevity-regulating genes in short-lived model organisms, such as yeast, worms and flies. These studies have revealed remarkable conservation of longevity-regulating genes and their networks among species. Decreased insulin/IGF-like signalling and decreased target of rapamycin (TOR) signalling are both shown to extend lifespan in evolutionarily divergent species, from unicellular organisms to mammals. Intriguingly, most of these longevity-regulating pathways reveal pro-longevity and anti-longevity effects on lifespan, depending on biological and environmental contexts. This review summarizes pleiotropic functions of the conserved longevity-regulating genes or pathways, focusing on studies in C. elegans.
Model Organism
Cite
Citations (9)
Model Organism
Melanogaster
Cite
Citations (1)
The fruit fly Drosophila melanogaster has become a valuable model organism in nutritional science, which can be applied to elucidate the physiology and the biological function of nutrients, including trace elements. Importantly, the application of chemically defined diets enables the supply of trace elements for nutritional studies under highly standardized dietary conditions. Thus, the bioavailability and bioactivity of trace elements can be systematically monitored in D. melanogaster. Numerous studies have already revealed that central aspects of trace element homeostasis are evolutionary conserved among the fruit fly and mammalian species. While there is sufficient evidence of vital functions of boron (B) in plants, there is also evidence regarding its bioactivity in animals and humans. Lithium (Li) is well known for its role in the therapy of bipolar disorder. Furthermore, recent findings suggest beneficial effects of Li regarding neuroprotection as well as healthy ageing and longevity in D. melanogaster. However, no specific essential function in the animal kingdom has been found for either of the two elements so far. Here, we summarize the current knowledge of Li and B bioactivity in D. melanogaster in the context of health and disease prevention.
Model Organism
Melanogaster
Cite
Citations (10)
Model Organism
Melanogaster
genetic model
Model system
Cite
Citations (19)
AbstractThe fruit fly Drosophila melanogaster is a powerful genetic model organism, which has been instrumental in the determination of essential developmental and neurological pathways conserved from invertebrates to humans. With the completion of both the human and Drosophila genomes, the revelation that we are more similar to this simple organism than previously suspected was realised. 75% of human genetic disease genes have clear homologues in the fly. By utilising an array of genetic tools available to disrupt or misexpress these proteins, it is now feasible to perform large-scale genetic screens in Drosophila to identify other members of a particular human genetic pathway. This review outlines some of the reasons Drosophila is a useful tool for the discovery of therapeutic targets, covers some of the tools available to manipulate this organism and discusses specific examples of how to use Drosophila as a genetic test tube for revealing proteins which act in a common pathway.Keywordscross-genomicsdisease modelsDrosophilamodel organisms
Model Organism
Genetic screen
Human disease
Cite
Citations (40)
The common fruit fly, Drosophila melanogaster, has been used to study human disease as a model organism for many years. Many basic biological, physiological, and neurological properties are conserved between mammals and fly. Moreover, Drosophila melanogaster has its unique advantage as a model organism. Recent studies showed that the high level of signaling pathway conservation in tumorigenesis between fly and human and its feasible genetic operation make fly an effective model for oncology research. Numerous research findings showed Drosophila melanogaster was an ideal model for studying the molecular mechanisms of tumorigenesis, invasion and metastasis. This review mainly focuses on the advantages of Drosophila melanogaster in cancer research, established models used for the research of specific cancers and prospective research direction of oncology. It is hoped that this paper can provide insight for cancer research and development of anti-cancer drugs.
Model Organism
Melanogaster
Cite
Citations (5)
Drosophila melanogaster has been widely used in the biological sciences as a model organism. Drosophila has a relatively short life span of 60-80 days, which makes it attractive for life span studies. Moreover, approximately 60% of the fruit fly genes are orthologs to mammals. Thus, metabolic and signal transduction pathways are highly conserved. Maintenance and reproduction of Drosophila do not require sophisticated equipment and are rather cheap. Furthermore, there are fewer ethical issues involved in experimental Drosophila research compared with studies in laboratory rodents, such as rats and mice. Drosophila is increasingly recognized as a model organism in food and nutrition research. Drosophila is often fed complex solid diets based on yeast, corn, and agar. There are also so-called holidic diets available that are defined in terms of their amino acid, fatty acid, carbohydrate, vitamin, mineral, and trace element compositions. Feed intake, body composition, locomotor activity, intestinal barrier function, microbiota, cognition, fertility, aging, and life span can be systematically determined in Drosophila in response to dietary factors. Furthermore, diet-induced pathophysiological mechanisms including inflammation and stress responses may be evaluated in the fly under defined experimental conditions. Here, we critically evaluate Drosophila melanogaster as a versatile model organism in experimental food and nutrition research, review the corresponding data in the literature, and make suggestions for future directions of research.
Model Organism
Cite
Citations (86)
Research on longevity and healthy aging promises to increase our lifespan and decrease the burden of degenerative diseases with important social and economic effects. Many aging theories have been proposed, and important aging pathways have been discovered. Model organisms have had a crucial role in this process because of their short lifespan, cheap maintenance, and manipulation possibilities. Yeasts, worms, fruit flies, or mammalian models such as mice, monkeys, and recently, dogs, have helped shed light on aging processes. Genes and molecular mechanisms that were found to be critical in simple eukaryotic cells and species have been confirmed in humans mainly by the functional analysis of mammalian orthologues. Here, we review conserved aging mechanisms discovered in different model systems that are implicated in human longevity as well and that could be the target of anti-aging interventions in human.
Model Organism
Healthy aging
Cite
Citations (89)