title: The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning.
abstract: Anaplastic Lymphoma Kinase (Alk) is a Receptor Tyrosine Kinase (RTK) activated in several cancers, but with largely unknown physiological functions. We report two unexpected roles for the Drosophila ortholog dAlk, in body size determination and associative learning. Remarkably, reducing neuronal dAlk activity increased body size and enhanced associative learning, suggesting that its activation is inhibitory in both processes. Consistently, dAlk activation reduced body size and caused learning deficits resembling phenotypes of null mutations in dNf1, the Ras GTPase Activating Protein-encoding conserved ortholog of the Neurofibromatosis type 1 (NF1) disease gene. We show that dAlk and dNf1 co-localize extensively and interact functionally in the nervous system. Importantly, genetic or pharmacological inhibition of dAlk rescued the reduced body size, adult learning deficits, and Extracellular-Regulated-Kinase (ERK) overactivation dNf1 mutant phenotypes. These results identify dAlk as an upstream activator of dNf1-regulated Ras signaling responsible for several dNf1 defects, and they implicate human Alk as a potential therapeutic target in NF1.
authors.affiliation: Institute of Cellular and Developmental Biology, Biomedical Sciences Research Centre "Alexander Fleming," Vari, Greece.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Gouzi
authors.forename: Anastasios
authors.initials: A
authors.lastname: Moressis
authors.forename: James A
authors.initials: JA
authors.lastname: Walker
authors.forename: Anthi A
authors.initials: AA
authors.lastname: Apostolopoulou
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Palmer
authors.forename: André
authors.initials: A
authors.lastname: Bernards
authors.forename: Efthimios M C
authors.initials: EM
authors.lastname: Skoulakis
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001245:Association Learning; D049628:Body Size / Q000235:genetics; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D058990:Molecular Targeted Therapy; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C105590:NF1 protein, Drosophila; D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D020703:ras GTPase-Activating Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases