Developmental defects and rescue from glucose intolerance of a catalytically-inactive novel Ship2 mutant mouse
(2012) Cellular Signalling — Vol. 24, n° 11, p. 1971-1980 (2012)
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- The function of the phosphoinositide 5-phosphatase Ship2 was investigated in a new mouse model expressing a germline catalytically-inactive Ship2<sup>Δ/Δ</sup> mutant protein. Ship2<sup>Δ/Δ</sup> 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<sup>D933A/+</sup> 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<sup>Δ/Δ</sup> phenotype had a dominant effect over the p110α<sup>D933A/+</sup> phenotype and, sometimes, there was a surprising additive effect of both mutations. p110α<sup>D933A/+</sup>Ship2<sup>Δ/Δ</sup> 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<sup>Δ/Δ</sup> mice. Together, our results suggest that the Ship2<sup>Δ/Δ</sup> 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. © 2012 Elsevier Inc.
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Dubois, E., Jacoby, M., Blockmans, M., Pernot, E., Schiffmann, S. N., Foukas, L. C., Henquin, J.-C., Vanhaesebroeck, B., Erneux, C., & Schurmans, S. (2012). Developmental defects and rescue from glucose intolerance of a catalytically-inactive novel Ship2 mutant mouse. Cellular Signalling, 24(11), 1971-1980. https://doi.org/10.1016/j.cellsig.2012.06.012 (Original work published 2012)