title: Developmental defects and rescue from glucose intolerance of a catalytically-inactive novel Ship2 mutant mouse.
abstract: The function of the phosphoinositide 5-phosphatase Ship2 was investigated in a new mouse model expressing a germline catalytically-inactive Ship2(∆/∆) mutant protein. Ship2(∆/∆) mice were viable with defects in somatic growth and in development of muscle, adipose tissue and female genital tract. Lipid metabolism and insulin secretion were also affected in these mice, but glucose tolerance, insulin sensitivity and insulin-induced PKB phosphorylation were not. We expected that the expression of the catalytically inactive Ship2 protein in PI 3'-kinase-defective p110α(D933A/+) mice would counterbalance the phenotypes of parental mice by restoring normal PKB signaling but, for most of the parameters tested, this was not the case. Indeed, often, the Ship2(∆/∆) phenotype had a dominant effect over the p110α(D933A/+) phenotype and, sometimes, there was a surprising additive effect of both mutations. p110α(D933A/+)Ship2(∆/∆) mice still displayed a reduced PKB phosphorylation in response to insulin, compared to wild type mice yet had a normal glucose tolerance and insulin sensitivity, like the Ship2(∆/∆) mice. Together, our results suggest that the Ship2(∆/∆) phenotype is not dependent on an overstimulated class I PI 3-kinase-PKB signaling pathway and thus, indirectly, that it may be more dependent on the lack of Ship2-produced phosphatidylinositol 3,4-bisphosphate and derived phosphoinositides.
authors: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors: Eléonore
authors: E
authors: Dubois
authors: Monique
authors: M
authors: Jacoby
authors: Marianne
authors: M
authors: Blockmans
authors: Eileen
authors: E
authors: Pernot
authors: Serge N
authors: SN
authors: Schiffmann
authors: Lazaros C
authors: LC
authors: Foukas
authors: Jean-Claude
authors: JC
authors: Henquin
authors: Bart
authors: B
authors: Vanhaesebroeck
authors: Christophe
authors: C
authors: Erneux
authors: Stéphane
authors: S
authors: Schurmans
mesh_terms: D000818:Animals; D055162:Biocatalysis; D001835:Body Weight; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018149:Glucose Intolerance / Q000378:metabolism* / Q000473:pathology; D000072181:Inositol Polyphosphate 5-Phosphatases; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D010641:Phenotype; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606435:Inppl1 protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases