Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice. Mol Endocrinol
Departments of Medicine, and Molecular and Cellular Pharmacology, University of California, San Francisco, California 94107-2140, USA. Molecular Endocrinology
(Impact Factor: 4.02).
12/2011; 25(12):2106-18. DOI: 10.1210/me.2010-0329
The phosphatidylinositol-3-kinase-dependent kinase, Akt2, plays a central role in mediating insulin effects in glucose-metabolizing tissues. Akt2 knockout mice display insulin resistance with a reactive increase in pancreatic islet mass and hyperinsulinemia. The related phosphatidylinositol-3-kinase-dependent kinase, serum- and glucocorticoid-regulated kinase 3 (SGK3), is essential for normal postnatal hair follicle development but plays no apparent role in glucose homeostasis. We report here an unexpected role of SGK3 in islet β-cell function, which is revealed in Akt2/SGK3 double-knockout (DKO) mice. DKO mice have markedly worse glucose homeostasis than Akt2 single-null animals, including greater baseline glucose, and greater rise in blood glucose after glucose challenge. However, surprisingly, our data strongly support the idea that this exacerbation of the glucose-handling defect is due to impaired β-cell function, rather than increased insulin resistance in peripheral tissues. DKO mice had lower plasma insulin and C-peptide levels, lower β-cell mass, reduced glucose-stimulated insulin secretion, and greater sensitivity to exogenous insulin than Akt2 single nulls. We further demonstrated that SGK3 is strongly expressed in normal mouse islets and, interestingly, that β-catenin expression is dramatically lower in the islets of DKO mice than in those of Akt2(-/-)/SGK3(+/+) or Akt2(-/-)/SGK3(+/-) mice. Taken together, these data strongly suggest that SGK3 plays a previously unappreciated role in glucose homeostasis, likely through direct effects within β-cells, to stimulate proliferation and insulin release, at least in part by controlling the expression and activity of β-catenin.
Available from: Karen E Sheppard
- "However, it is possible that the phenotype of the sgk1−/−/sgk3−/− mouse is not more severe as SGK2 may be able to compensate and maintain some level of homeostasis, despite no detectable increase of SGK2 transcript levels in these mice.113 Characterization of an akt2−/−/sgk3−/− mouse found that the defect in hair growth is markedly worse in the double knockout mice than in sgk3−/− mice only114 and that they have a markedly greater impairment of glucose homeostasis than Akt2−/− mice.115 Akt2−/− mice also displayed insulin resistance, hyperinsulinemia and increased β-cell proliferation and mass.116 "
[Show abstract] [Hide abstract]
ABSTRACT: The phosphoinositide 3-kinase (PI3-K) signaling pathway plays an important role in a wide variety of fundamental cellular processes, largely mediated via protein kinase B/v-akt murine thymoma viral oncogene homolog (PKB/AKT) signaling. Given the crucial role of PI3-K/AKT signaling in regulating processes such as cell growth, proliferation, and survival, it is not surprising that components of this pathway are frequently dysregulated in cancer, making the AKT kinase family members important therapeutic targets. The large number of clinical trials currently evaluating PI3-K pathway inhibitors as a therapeutic strategy further emphasizes this. The serum- and glucocorticoid-inducible protein kinase (SGK) family is made up of three isoforms, SGK1, 2, and 3, that are PI3-K-dependent, serine/threonine kinases, with similar substrate specificity to AKT. Consequently, the SGK family also regulates similar cell processes to the AKT kinases, including cell proliferation and survival. Importantly, there is emerging evidence demonstrating that SGK3 plays a critical role in AKT-independent oncogenic signaling. This review will focus on the role of SGK3 as a key effector of AKT-independent PI3-K oncogenic signaling.
Available from: Annette Khaled
- "When AKT2 knockout mice were mated with mice deficient in serum- and glucocorticoid-regulated kinase 3 (SGK3) gene, an unexpected role was observed for SGK3 in islet β-cell function . Double-knockout mice had worse glucose homeostasis than AKT2 null mice, including higher baseline glucose and increased blood glucose after glucose challenge. "
[Show abstract] [Hide abstract]
ABSTRACT: The AKT family of serine threonine kinases is of critical importance with regard to growth factor signaling, cell proliferation, survival and oncogenesis. Engagement of signaling receptors induces the lipid kinase, phosphatidylinositol 3-kinase (PI3K), which enables the activation of AKT. Responsive to the PI3K/AKT pathway is the mammalian target of rapamycin (mTOR), a major effector that is specifically implicated in the regulation of cell growth as a result of nutrient availability and cellular bioenergetics. These kinases mediate the activity of a multitude of intracellular signaling molecules and intersect with multiple pathways that regulate cellular processes. Elucidating the role of AKT/mTOR in metabolism and in hallmark signaling pathways that are aberrantly affected in cancer has provided a solid foundation of discoveries. From this, new research directions are emerging with regard to the role of AKT/mTOR in diabetes and T cell-mediated immunity. As a result, a new perspective is developing in how AKT/mTOR functions within intracellular signaling pathways to maintain cellular homeostasis. An appreciation is emerging that altered equilibrium of AKT/mTOR pathways contributes to disease and malignancy. Such new insights may lead to novel intervention strategies that may be useful to reprogram or reset the balance of intracellular signaling.
[Show abstract] [Hide abstract]
ABSTRACT: The peptide hormone arginine vasopressin (AVP) plays a critical role in regulating salt and water transport in the mammalian kidney. Recent studies have also demonstrated that AVP can promote cell survival in neuronal cells through V1 receptors. The current study addresses whether AVP can inhibit apoptosis in kidney collecting duct cells via V2 receptors and also explores the downstream signaling pathways regulating this phenomenon. TUNEL analysis and caspase cleavage assays demonstrated that 1-desamino-8-d-arginine vasopressin (dDAVP) inhibited apoptosis induced by various agents (staurosporine, actinomycin D, and cycloheximide) in cultured mouse cortical collecting duct cells (mpkCCD). Incubation with dDAVP also inhibited apoptosis induced by the phosphatidylinositol 3-kinase (PI3K) pathway inhibitor LY294002, suggesting that the anti-apoptotic effects of dDAVP are largely independent of PI3K signaling. The V2 receptor antagonist SR121463 completely abolished the anti-apoptotic effects of dDAVP. In addition, incubation with 8-cpt-cAMP, a cell permeable analog of cyclic AMP, reproduced the anti-apoptotic effects of dDAVP. Both dDAVP and 8-cpt-cAMP increased phosphorylation of pro-apoptotic Bcl-2 family members Bad and Bok. Bad phosphorylation at Ser-112 and Ser-155 is known to inhibit its pro-apoptotic activity. Pre-incubation with H89 blocked dDAVP-induced phosphorylation of both Bad and Bok suggesting dependence on protein kinase A (PKA). This study provides evidence that AVP can inhibit apoptosis through the V2 receptor and downstream cAMP-mediated pathways in mammalian kidney. The anti-apoptotic action of AVP may be relevant to a number of physiological and pathophysiological conditions including osmotic tolerance in the inner medulla, escape from AVP-induced anti-diuresis, and polycystic kidney disease.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.