title: Direct interaction of avermectin with epidermal growth factor receptor mediates the penetration resistance in Drosophila larvae.
abstract: With the widespread use of avermectins (AVMs) for managing parasitic and agricultural pests, the resistance of worms and insects to AVMs has emerged as a serious threat to human health and agriculture worldwide. The reduced penetration of AVMs is one of the main reasons for the development of the resistance to the chemicals. However, the detailed molecular mechanisms remain elusive. Here, we use the larvae of Drosophila melanogaster as the model organism to explore the molecular mechanisms underlying the development of penetration resistance to AVMs. We clearly show that the chitin layer is thickened and the efflux transporter P-glycoprotein (P-gp) is overexpressed in the AVM-resistant larvae epidermis. We reveal that the activation of the transcription factor Relish by the over-activated epidermal growth factor receptor (EGFR)/AKT/ERK pathway induces the overexpression of the chitin synthases DmeCHS1/2 and P-gp in the resistant larvae. Interestingly, we discover for the first time, to the best of our knowledge, that AVM directly interacts with EGFR and leads to the activation of the EGFR/AKT/ERK pathway, which activates the transcription factor Relish and induces the overexpression of DmeCHS1/2 and P-gp. These findings provide new insights into the molecular mechanisms underlying the development of penetration resistance to drugs.
authors.affiliation: Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China.
authors.forename: Pan
authors.initials: P
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China Department of Veterinary Medicine and Animal Science, Beijing Agriculture College, Beijing 102206, People's Republic of China.
authors.forename: Ying-Jian
authors.initials: YJ
authors.lastname: Sun
authors.affiliation: Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China wuyj@ioz.ac.cn.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Wu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D002687:Chitin Synthase / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007305:Insecticide Resistance / Q000187:drug effects*; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D007814:Larva / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D029721:Drosophila Proteins; C101626:Rel protein, Drosophila; D014157:Transcription Factors; D007559:Ivermectin; C019264:avermectin; D002687:Chitin Synthase; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: DmeCHS1/2; Drosophila melanogaster larvae; EGFR; avermectin; penetration resistance