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GSK can function in regulating insulin
GSK-3 can function in regulating insulin signaling and glucose metabolism. Inactivation of GSK-3 activity results in dephosphorylation and activation of GS that leads to improved glucose tolerance. However, there are additional mechanisms that can lead to increases in GS activity and improve insulin-resistance. Insulin-resistance is very important in the development and establishment of type 2 TH-302 receptor [31]. Type 2 diabetes is increasing at an alarming rate in developed countries due to the increase in obesity, especially among children in the western world.
GSK-3 is important in glucose homeostasis. GSK-3 inhibitors stimulate GS and glucose uptake in tissue culture models and pre-diabetic obese rats [32], [33]. Treatment of diabetic Zucker rats with some GSK-3 inhibitors (CT118637, CHIR98014 and CHIR99021) elicited dramatic improvement of oral glucose tolerance and insulin sensitivity. Treatment with the GSK-3 inhibitors enhanced insulin receptor substrate-1 (IRS-1) dependent insulin receptor (IR) signaling in skeletal muscle. There were improvements in dyslipidemia and whole body insulin sensitivity after treatment with the GSK-3 inhibitors [33].
Overview of pathology of key cancers discussed in this review with relevance to GSK-3 and associated signaling pathways
Regulation of GSK-3 activity by the PI3K/PTEN/Akt/mTORC1 and Ras/Raf/MEK/ERK signaling pathways
An overview of the kinases and phosphatases that regulate GSK-3 activity and a few of the downstream targets are presented in Fig. 1. Multiple signaling molecules can regulate GSK-3 activity. One of the best studied regulators of GSK-3 is Akt which lies in the PI3K/PTEN/Akt/mTORC1 pathway [148], [149]. Akt is a S/T kinase that also phosphorylates many key proteins involved in the regulation of cell growth and apoptosis [148], [149], [150], [151], [152], [153], [154], [155]. Upon ligand activation of growth factor (GF) receptors, the PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK and other pathways become activated. Akt activation can serve to phosphorylate GSK-3 that leads to its inactivation. A diagram illustrating the interactions of GSK-3 with the PI3K/PTEN/Akt/mTORC1 and Ras/Raf/MEK/ERK pathways is presented in Fig. 2.
Other kinases can phosphorylate GSK-3 to regulate its activity [156], [157], [158], [159], [160], [161], [162], [163], [164]. These include protein kinase A [156], mitogen activated kinase [aka extracellular regulated kinase 1,2 (ERK1,2)] [157], and p38MAPK[161]. In addition, GSK-3 can be regulated by tyrosine (Y) kinases such as Src, the protein tyrosine kinase 2 beta (PYK2) [158], [159] and Fyn [160]. GSK-3 can be also regulated by dephosphorylation by protein phosphatases including: protein phosphatase 2A (PP2A) and PP1 [165]. GSK-3 may also autophosphorylate itself [162]. GSK-3 can regulate many proteins including: p70S6K [166], Rictor [167] cyclin D [168], [169], cyclin E [170], focal adhesion kinase (FAK) [171], Snail [172], [173], myeloid cell leukemia sequence 1 (Mcl-1) [174], BCL2-Like 12 (Bcl2L12) [175], PTEN [176], insulin receptor substrate 1(IRS1) [177], and tuberous sclerosis complex 2 (TSC2) [178].
Ras can activate GSK-3beta by stimulation of the Raf/MEK/ERK cascade and activation of the v-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 1 (ETS) transcription factor (see Fig. 2). GSK-3 can then stimulate NF-kappaB expression that influences the expression of multiple genes. GSK-3 can also phosphorylate PTEN and IRS-1 that inhibits their activity [176], [177]. GSK-3 can phosphorylate TSC2 which enhances its activity and serves to suppress mTORC1 activity [178]. During cell stress, GSK-3beta can phosphorylate Rictor at serine-1235 that inhibits the binding of Akt to mTORC2. In the absence of functional mTORC2 activity, Akt is not fully activated. Thus while Akt can negatively regulate GSK-3 activity, GSK-3 can under certain circumstances return the favor and suppress Akt activation.
Interactions of GSK-3 and the Wnt signaling pathway