title: Abnormal elevated PTEN expression in the mouse antrum of a model of GIST Kit(K641E/K641E).
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Approximately 85% of GISTs harbor activating mutations of the KIT or PDGFRA receptor tyrosine kinases. PTEN and SHIP2 are major phosphatases that dephosphorylate PI(3,4,5)P(3), one of the intracellular signal pathways downstream of KIT. PTEN is an important tumor suppressor, whereas the involvement of SHIP2 in cancer has been proposed based essentially on cell line studies. We have used a mouse model of GIST, i.e. Kit(K641E) knock-in mice, resulting in the substitution of a Lys by Glu at position 641 of Kit. In homozygous Kit(K641E) mice, PTEN-immunoreactivity (ir) in antrum was found in the hyperplastic Kit-ir layer. The same localization was found for SHIP2. Western blot analysis in antrum showed a large increase in PTEN expression in Kit(K641E) homozygous mice as compared to wild type. In contrast, SHIP2 expression was not affected between the two genotypes. Erk1, but not PKB, phosphorylation appears to be upregulated in Kit(K641E) homozygous mice. In the human GIST882 imatinib sensitive cell line, both PTEN and SHIP2 were expressed and showed, in part, a nuclear localization. The upregulation of PTEN in antrum in Kit(K641E) mice might serve as a feedback mechanism to limit PI 3-kinase activation downstream of Kit in a context of oncogenic mutation.
authors.affiliation: Institut de Recherche Interdisciplinaire (IRIBHM), Université Libre de Bruxelles, Campus Erasme, Bldg. C, 808 Route de Lennik, 1070 Brussels, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Deneubourg
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ralea
authors.forename: Petra
authors.initials: P
authors.lastname: Gromova
authors.forename: Ramon
authors.initials: R
authors.lastname: Parsons
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Vanderwinden
authors.forename: Christophe
authors.initials: C
authors.lastname: Erneux
mesh_terms: D000818:Animals; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques; D006720:Homozygote; D006801:Humans; D000068877:Imatinib Mesylate; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011706:Pyloric Antrum / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C000606435:Inppl1 protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases