Unravelling the activation mechanisms of protein kinase B/Akt

Scheid, Michael P.; Woodgett, James R.

doi:10.1016/s0014-5793(03)00562-3

Cited by 362 publications

(330 citation statements)

References 41 publications

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“…These results once again lend support to the growing appreciation that apoptosis and inflammation are not mutually exclusive but may be linked. In addition, the Akt phosphorylated on serine 473, which is the first step toward its membrane association and full activation [48,49], was significantly increased by fB deficiency, which may have contributed to the reduction in apoptosis observed in these studies. Furthermore, MRL/lpr mice had significantly greater quantities of p-PTEN (serine 380) than fB -/-MRL/lpr mice.…”

Section: Behavioral Changes In Mrl/lpr Mice Are Complement Dependentmentioning

confidence: 75%

Absence of functional alternative complement pathway alleviates lupus cerebritis

et al. 2007

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The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB -/-MRL/lpr) compared to fBsufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16 AE 0.02 vs. 0.35 AE 0.13, p <0.03) was increased, while expression of p-PTEN (0.40 AE 0.06 vs. 0.11 AE 0.07, p <0.05) was decreased in fB -/-MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB -/-MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis. IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disease, with central nervous system (CNS) involvement occurring in 20-70% of patients. Complement activation is believed to play a key role in the pathogenesis of SLE [1]. The relevance of complement in lupus cerebritis is supported by enhanced C3 and C4 index values in the cerebrospinal fluid of patients [2] and increased levels of the anaphylatoxins, C3a and C5a, which correlate with the CNS flares [3]. This is also true in experimental lupus cerebritis, and is supported by our recent studies, in which systemic inhibition of the C3/C5 convertases reduced pathological alterations in the CNS of the lupus mouse model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice [4,5]. Complement can be activated through classical, alternative and lectin pathways. Complement factor B (fB) is a key protein required for the activation of the alternative pathway [6] and is increased in circulation and in tissues of lupus mice [7][8][9]. In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes 15]. Mice with targeted deletion of the fB gene (fB -/-) were protected from lupus nephritis and ischemiareperfusion injury [7,16]. However, the role of fB in the pathogenesis of lupus cerebritis has not been defined. Bb, one of the split products of fB, can induce apoptosis [17], which is a key feature in the brains of MRL/lpr mice [5,18]. Apoptosis can also be induced by several other factors such as nitric oxide (NO), edema, and the extracellular matrix (ECM) proteins through integrin si...

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Section: Behavioral Changes In Mrl/lpr Mice Are Complement Dependentmentioning

confidence: 75%

Absence of functional alternative complement pathway alleviates lupus cerebritis

et al. 2007

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“…Phosphorylated Ser 473 serves as a docking site for PDK1 to phosphorylate Thr 308 34, 35. As shown in Figure 5A (Fig.…”

Section: Resultsmentioning

confidence: 98%

Rictor regulates the vasculogenic mimicry of melanoma via the AKT‐MMP‐2/9 pathway

Liang

Sun

Zhao

et al. 2017

J Cellular Molecular Medi

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Vasculogenic mimicry (VM)‐positive melanomas are usually associated with poor prognosis. Rictor, the key component of the rapamycin‐insensitive complex of mTOR (mTORC2), is up‐regulated in several cancers, especially in melanomas with poor prognosis. The aim of this study was to investigate the role of Rictor in the regulation of VM and the mechanism underlying this possible regulation. VM channels were found in 35 of 81 tested melanoma samples and high Rictor expression correlated with VM structures. Moreover, Kaplan–Meier survival curves indicated that VM structures and high Rictor expression correlated with shorter survival in patients with melanoma. In vitro, Rictor knockdown by short hairpin RNA (shRNA) significantly inhibited the ability of A375 and MUM‐2B melanoma cells to form VM structures, as evidenced by most tubes remaining open. Cell cycle analysis revealed that Rictor knockdown blocked cell growth and resulted in the accumulation of cells in G2/M phase, and cell migration and invasion were greatly affected after Rictor down‐regulation. Western blotting assays indicated that down‐regulating Rictor significantly inhibited the phosphorylation of AKT at Ser473 and Thr308, which subsequently inhibited the expression and activity of downstream MMP‐2/9, as confirmed by real‐time PCR and gelatin Zymography. MK‐2206, a small‐molecule inhibitor of AKT, similarly inhibited the activity of AKT and secretion of MMP‐2/9, further supporting that Rictor down‐regulation inhibits the phosphorylation of AKT and activity of downstream MMP‐2/9 to affect VM formation. In conclusion, Rictor plays an important role in melanoma VM via the Rictor—AKT—MMP‐2/9 signalling pathway.

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“…Neuron survival is promoted by the AKT protein kinase (Das et al, 2007), a serine/threonine protein kinase (reviewed by Manning & Cantley, 2007). Active AKT is phosphorylated at threonine 308 and serine 473 (Scheid & Woodgett, 2003). AKT can phosphorylate and regulate several pro-or anti-apoptotic proteins (reviewed by Cooray, 2004), supporting a role for AKT during apoptosis and neuronal differentiation.…”

Section: Introductionmentioning

confidence: 99%

Herpes simplex virus type 1 latency-associated transcript inhibits apoptosis and promotes neurite sprouting in neuroblastoma cells following serum starvation by maintaining protein kinase B (AKT) levels

Carpenter

Hsiang

et al. 2009

Journal of General Virology

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The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is expressed abundantly in latently infected sensory neurons. LAT-deletion-mutant virus strains have reducedreactivation phenotypes in small animal models of infection, demonstrating that LAT plays an important role in the latency-reactivation cycle of HSV-1. Previous studies demonstrated that the anti-apoptosis functions of LAT are important for regulating the latency-reactivation cycle because three different anti-apoptosis genes can substitute for LAT. Although LAT inhibits caspase 3 activation, the signalling pathway by which LAT inhibits caspase 3 activation was not identified. In this study, we analysed mouse neuroblastoma cells (C1300) that express LAT stably (DC-LAT6 cells) following serum starvation. As expected, DC-LAT6 cells were resistant to apoptosis following serum withdrawal. Levels of total and phosphorylated AKT (protein kinase B), a serine/threonine protein kinase that promotes cell survival, were higher in DC-LAT6 cells after serum withdrawal than in C1300 cells or a cell line stably transfected with a LAT promoter mutant (DC-DLAT311). A specific AKT inhibitor reduced the anti-apoptosis functions of LAT and phosphorylated AKT levels. After serum withdrawal, more DC-LAT6 cells sprouted neurites and exhibited a differentiated morphology. NeuN (neuronal nuclei), a neuron-specific nuclear protein, was expressed abundantly in DC-LAT6 cells, but not C1300 cells, after serum withdrawal, further supporting the concept that LAT enhanced neuronal-like morphology. Collectively, these studies suggested that LAT, directly or indirectly, maintained total and phosphorylated AKT levels, which correlated with increased cell survival and mature neuronal-like morphology.

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Unravelling the activation mechanisms of protein kinase B/Akt

Cited by 362 publications

References 41 publications

Absence of functional alternative complement pathway alleviates lupus cerebritis

Absence of functional alternative complement pathway alleviates lupus cerebritis

Rictor regulates the vasculogenic mimicry of melanoma via the AKT‐MMP‐2/9 pathway

Herpes simplex virus type 1 latency-associated transcript inhibits apoptosis and promotes neurite sprouting in neuroblastoma cells following serum starvation by maintaining protein kinase B (AKT) levels

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