title: Characterization of a novel five-transmembrane domain cholecystokinin-2 receptor splice variant identified in human tumors.
abstract: The cholecystokinin-2 receptor (CCK2R), is expressed in cancers where it contributes to tumor progression. The CCK2R is over-expressed in a sub-set of tumors, allowing its use in tumor targeting with a radiolabel ligand. Since discrepancies between mRNA levels and CCK2R binding sites were noticed, we searched for abnormally spliced variants in tumors from various origins having been previously reported to frequently express cholecystokinin receptors, such as medullary thyroid carcinomas, gastrointestinal stromal tumors, leiomyomas and leiomyosarcomas, and gastroenteropancreatic tumors. A variant of the CCK2R coding for a putative five-transmembrane domains receptor has been cloned. This variant represented as much as 6% of CCK2R levels. Ectopic expression in COS-7 cells revealed that this variant lacks biological activity due to its sequestration in endoplasmic reticulum. When co-expressed with the CCK2R, this variant diminished membrane density of the CCK2R and CCK2R-mediated activity (phospholipase-C and ERK activation). In conclusion, a novel splice variant acting as a dominant negative on membrane density of the CCK2R may be of importance for the pathophysiology of certain tumors and for their in vivo CCK2R-targeting.
authors: Université de Toulouse 3, EA 4552 Toulouse, France.
authors: Claire
authors: C
authors: Sanchez
authors: Chantal
authors: C
authors: Escrieut
authors: Pascal
authors: P
authors: Clerc
authors: Véronique
authors: V
authors: Gigoux
authors: Beatrice
authors: B
authors: Waser
authors: Jean Claude
authors: JC
authors: Reubi
authors: Daniel
authors: D
authors: Fourmy
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D018276:Carcinoma, Medullary / Q000378:metabolism; D002522:Chlorocebus aethiops; D002766:Cholecystokinin / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005755:Gastrins / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000378:metabolism; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism; D006801:Humans; D007340:Insulinoma / Q000378:metabolism; D007889:Leiomyoma / Q000378:metabolism; D007890:Leiomyosarcoma / Q000378:metabolism; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis; D043887:Receptor, Cholecystokinin B / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D005755:Gastrins; D012333:RNA, Messenger; D043887:Receptor, Cholecystokinin B; D002766:Cholecystokinin; D048049:Extracellular Signal-Regulated MAP Kinases; D010738:Type C Phospholipases