The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB

Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, 60607, USA.
Experimental Cell Research (Impact Factor: 3.25). 12/1999; 253(1):210-29. DOI: 10.1006/excr.1999.4690
Source: PubMed


The serine/threonine kinase Akt, or protein kinase B (PKB), has recently been a focus of intense research. It appears that Akt/PKB lies in the crossroads of multiple cellular signaling pathways and acts as a transducer of many functions initiated by growth factor receptors that activate phosphatidylinositol 3-kinase (PI 3-kinase). Akt/PKB is particularly important in mediating several metabolic actions of insulin. Another major activity of Akt/PKB is to mediate cell survival. In addition, the recent discovery of the tumor suppressor PTEN as an antagonist of PI 3-kinase and Akt/PKB kinase activity suggests that Akt/PKB is a critical factor in the genesis of cancer. Thus, elucidation of the mechanisms of Akt/PKB regulation and its physiological functions should be important for the understanding of cellular metabolism, apoptosis, and cancer.

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Available from: Eugene S Kandel, Jan 23, 2015
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    • "The authors of these reports, however, did not study expression of NgR in oligodendrocyte lineage cells, but did highlight the expression and role of LINGO-1 on neurons and mature oligodendrocytes. They showed that expression of LINGO-1, similar to its co-receptor NgR on neurons, can inhibit axonal regeneration by activation of RhoA signaling pathway; though LINGO-1 function on oligodendrocyte was not mediated through binding to NgR [65]–[67]. Huang et al. (2012); however, suggested that antagonizing NgR in vitro increased the number of PDGFRα+ OPCs and prolonged their processes but hampered their differentiation. They suggested that the effect of myelin inhibitory factors on OPC differentiation and process extending via NgR expressed by OPCs were mainly mediated via Erk1/2 and PI3/Akt signaling pathways and also involved various cell proliferation and differentiation effects [68], [69], including oligodendrocyte differentiation [17]. "
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    ABSTRACT: Background Inhibitory factors have been implicated in the failure of remyelination in demyelinating diseases. Myelin associated inhibitors act through a common receptor called Nogo receptor (NgR) that plays critical inhibitory roles in CNS plasticity. Here we investigated the effects of abrogating NgR inhibition in a non-immune model of focal demyelination in adult mouse optic chiasm. Methodology/Principal Findings A focal area of demyelination was induced in adult mouse optic chiasm by microinjection of lysolecithin. To knock down NgR levels, siRNAs against NgR were intracerebroventricularly administered via a permanent cannula over 14 days, Functional changes were monitored by electrophysiological recording of latency of visual evoked potentials (VEPs). Histological analysis was carried out 3, 7 and 14 days post demyelination lesion. To assess the effect of NgR inhibition on precursor cell repopulation, BrdU was administered to the animals prior to the demyelination induction. Inhibition of NgR significantly restored VEPs responses following optic chiasm demyelination. These findings were confirmed histologically by myelin specific staining. siNgR application resulted in a smaller lesion size compared to control. NgR inhibition significantly increased the numbers of BrdU+/Olig2+ progenitor cells in the lesioned area and in the neurogenic zone of the third ventricle. These progenitor cells (Olig2+ or GFAP+) migrated away from this area as a function of time. Conclusions/Significance Our results show that inhibition of NgR facilitate myelin repair in the demyelinated chiasm, with enhanced recruitment of proliferating cells to the lesion site. Thus, antagonizing NgR function could have therapeutic potential for demyelinating disorders such as Multiple Sclerosis.
    PLoS ONE 09/2014; 9(9):e106378. DOI:10.1371/journal.pone.0106378 · 3.23 Impact Factor
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    • "To estimate the time course of activation of PKB, we measured the phosphorylation of PKB at its activation sites Thr308 and Ser473 (25). In agreement with the work of Miyaziki et al. (30), we also saw significant increases in the phosphorylation of PKB 3 days following overload in rats (Fig. 4A). "
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    ABSTRACT: The goal of the current work was to profile positive (mTORC1 activation, autocrine/paracrine growth factors) and negative [AMPK, unfolded protein response (UPR)] pathways that might regulate overload-induced mTORC1 activation with the hypothesis that a number of negative regulators of mTORC1 will be engaged during a supra-physiological model of hypertrophy. To achieve this, mTORC1-IRS1/2 signaling, BiP/CHOP/IRE1α, and AMPK activation were determined in rat plantaris muscle following synergist ablation (SA). SA resulted in significant increases in muscle mass of ~4% per day throughout the 21 days of the experiment. The expression of the insulin-like growth factors were high throughout the 21d of overload. However, IGF signaling was limited since IRS1 and 2 were undetectable in the overloaded muscle from day 3 to day 9. The decreases in IRS1/2 protein were paralleled by increases in GRB10(Ser501/503) and S6K1(Thr389) phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB(Ser473) phosphorylation was higher from 3-6 days and this was associated with increased TSC2(Thr939) phosphorylation. The phosphorylation of TSC2(Thr1345) (an AMPK site) was also elevated whereas phosphorylation at the other PKB site, Thr(1462), was unchanged at 6d. In agreement with the phosphorylation of Thr(1345), synergist ablation led to activation of α1-AMPK during the initial growth phase, lasting the first 9 days before returning to baseline by day 12. The UPR markers CHOP and BiP were elevated over the first 12 days following ablation, whereas IRE1α levels decreased. These data suggest that during supra-physiological muscle loading, at least three potential molecular brakes engage to down-regulate mTORC1.
    AJP Endocrinology and Metabolism 06/2014; 307(4). DOI:10.1152/ajpendo.00674.2013 · 3.79 Impact Factor
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    • "This study demonstrates that, in addition to inducing apoptosis, PPY also inhibits the PI3K/Akt pathway in MCF-7 cells. The PI3K/Akt pathway has been identified as key player in cell survival (23,24). Akt also functions in normal growth, as evidenced by Akt-knockout mice, which show retarded growth (25,26). "
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    ABSTRACT: This study examined how PPY, a peptide from Porphyra yezoensis, regulates multiple cell growth-related signaling pathways in MCF-7 cells. This study determined that PPY induces cell cycle arrest and inhibits the IGF-IR signaling pathway. Cell proliferation studies revealed that PPY induced cell death in a dose-dependent manner. Expression levels of IGF-IR were decreased in MCF-7 cells by PPY in a dose‑dependent manner. These results indicate that inhibition of the IGF-IR pathway is also involved in PPY induced proliferation of MCF-7 cells. In addition, these data demonstrated that PPY induces cell cycle arrest and activates apoptosis.
    International Journal of Oncology 06/2014; 45(3). DOI:10.3892/ijo.2014.2509 · 3.03 Impact Factor
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