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Review
. 2009 Jul;20(5):243-51.
doi: 10.1016/j.tem.2009.03.002. Epub 2009 Jun 21.

Akt and PTEN: beta-cell mass and pancreas plasticity

Lynda Elghazi  1 , Ernesto Bernal-Mizrachi
Affiliations
Review

Akt and PTEN: beta-cell mass and pancreas plasticity

Lynda Elghazi et al. Trends Endocrinol Metab. 2009 Jul.

Abstract

The capacity of pancreatic beta-cells to adapt to insulin resistance is crucial for glucose homeostasis and is a factor in the development of type 2 diabetes. The insulin receptor substrate (insulin receptor 2/phosphoinositide 3-kinase [PI3K]) pathway plays a crucial part in regulating beta-cell mass and function. The serine-threonine kinase Akt, also known as protein kinase B, is one of the major downstream targets of the PI3K pathway and is negatively regulated by phosphatase and tensin homologue deleted on chromosome 10. This Akt signaling pathway has recently been implicated in cell-cycle progression and survival of pancreatic beta-cells. Understanding the mechanisms that link Akt to modulation of beta-cell mass, function and plasticity will positively affect treatment of human diabetes.

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Figures

Figure 1
Figure 1. Schematic representation of Akt/PKB activation and signaling
Activation of Akt signaling in β-cells occurs upon stimulation with Insulin growth factor (IGF)I, insulin, glucose, Hepatocyte growth factor (HGF), Fibroblast growth factor (FGF)21, Stromal derived factor (SDF), Obestatin and gut incretins such as Glucose-dependent insulinotropic polypeptide (GIP) and Glucagon like peptides (GLP), among others [90]. Akt activity is regulated at different levels via both Phosphoinositide 3-kinase (PI3K) dependent and independent mechanisms [72]. A critical step leading to activation of Akt is the generation of phosphatidylinositol (3,4,5) P3 phosphate (PIP3) by PI3K. PIP3 binding to the Pleckstrin homology-domain (PH) recruits Akt/PKB and phosphoinositide-dependent kinase-1 (PDK1) to the plasma membrane favoring phosphorylation of T308 (309 in AKT2 and 305 in AKT3). Phosphorylation of S473 by mTORC2 (mTor/Rictor/GβL) complex is necessary for full activation of Akt [91]. The inactivation of Akt/PKB signaling is mediated by protein phosphatase 2A (PP2A) and α isoform of PH-domain leucine-rich repeat phosphatase (PHLPP)-mediated dephosphorylation of T308 and S473 respectively. Another important mechanism that negatively regulates Akt/PKB activity is the dephosphorylation of PIP3 molecules by the phosphatase and Tensin homologue deleted on chromosome 10 (PTEN). Another level of regulation is achieved by binding to Akt-interacting proteins that lack significant kinase activity. These Akt interacting proteins include the mammalian homolog of Drosophila Tribbles (TRB3), and C-terminal modulator protein (cTMP) Akt phosphorylation enhancer (APE), Tcl-1 oncoprotein, c-Jun N-terminal kinase (JNK)–interacting protein 1 (JIP1), growth factor receptor–binding protein–10 (Grb10) among others. Akt activity can also be negatively regulated by c-Jun N-terminal kinase (JNK) after induction of oxidative stress, cytokines and ER stress, resulting in inhibition of Akt signaling and apoptosis. Recent evidence suggests that increased mTORC1 (mTOR/Raptor/GβL) signaling inhibits insulin signaling by phosphorylation of IRS1 and possibly IRS2 in a ribosomal S6 kinase (S6K)-dependent manner.
Figure 2
Figure 2. Schematic representation of various intracellular effects of Akt/PKB signaling
Upon activation, Akt phosphorylates numerous downstream targets that regulate diverse biological processes such as cell cycle progression, apoptosis, senescence, neogenesis, protein synthesis, cell size and insulin-mediated metabolism. This diagram illustrates a partial list of direct and indirect downstream effectors of Akt signaling. The green arrow demonstrates a direct stimulatory effect of Akt. The red horizontal bars demonstrate an inhibitory effect of Akt on the designated target. The arrows next to each molecule indicate upregulation (green) and downregulation (red).
See this image and copyright information in PMC

References

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