title: Prenylated Rab acceptor domain family member 1 is involved in stimulated ACTH secretion and inhibition.
abstract: Dexamethasone (Dex) inhibits stimulated adrenocorticotrophic hormone (ACTH) secretion in AtT-20 cells, a mouse corticotroph tumor cell line. Dexras1 protein expression is induced in corticotrophs by Dex. The function of Dexras1 is unknown; however, it may be involved in corticotrophic negative feedback. Here we report the identification of a Dexras1 interactor, prenylated Rab acceptor domain family member 1 (PRAF1), a protein that localizes to the Golgi complex, post-Golgi vesicles, and endosomes. We determined that amino acids 54-175 of PRAF1 are essential for interaction with Dexras1 and that specific point mutations located within this region enhance PRAF1-Dexras1 interactions. AtT-20 cells stably transfected with truncated or mutated PRAF1 constructs had altered responses to corticotrophin-releasing hormone and Dex, upregulated expression of the ACTH prohormone pro-opiomelanocortin (POMC), altered POMC processing, and altered Golgi complex morphology with decreased intra-Golgi and intracellular co-localization of PRAF1 and ACTH proteins. Our findings indicate that PRAF1 plays a novel role in ACTH stimulated secretion. We propose a model whereby Dexras1 interaction with PRAF1 may lock the sites necessary for PRAF1-Rab3A-VAMP2 interaction resulting in Dex-mediated inhibition of ACTH secretion.
authors.affiliation: Pioneer Valley Life Sciences Institute, Springfield, MA 01199, United States. Shannon.Compton2@baystatehealth.org
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Compton
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kemppainen
authors.forename: Ellen N
authors.initials: EN
authors.lastname: Behrend
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology*; D051379:Mice; D017354:Point Mutation; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; C498435:Rabac1 protein, mouse; D033921:Vesicular Transport Proteins; D011333:Pro-Opiomelanocortin; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; C498511:Rasd1 protein, mouse; D018631:ras Proteins