Abstract：
:Akt (also known as protein kinase B or PKB) comprises three closely related isoforms Akt1, Akt2 and Akt3 (or PKBα/β/γ respectively). We have a very good understanding of the mechanisms by which Akt isoforms are activated by growth factors and other extracellular stimuli as well as by oncogenic mutations in key upstream regulatory proteins including Ras, PI3-kinase subunits and PTEN. There are also an ever increasing number of Akt substrates being identified that play a role in the regulation of the diverse array of biological effects of activated Akt; this includes the regulation of cell proliferation, survival and metabolism. Dysregulation of Akt leads to diseases of major unmet medical need such as cancer, diabetes, cardiovascular and neurological diseases. As a result there has been substantial investment in the development of small molecular Akt inhibitors that act competitively with ATP or phospholipid binding, or allosterically. In this review we will briefly discuss our current understanding of how Akt isoforms are regulated, the substrate proteins they phosphorylate and how this integrates with the role of Akt in disease. We will furthermore discuss the types of Akt inhibitors that have been developed and are in clinical trials for human cancer, as well as speculate on potential on-target toxicities, such as disturbances of heart and vascular function, metabolism, memory and mood, which should be monitored very carefully during clinical trial.
journal_name
Cell Signaljournal_title
Cellular signallingauthors
Hers I,Vincent EE,Tavaré JMdoi
10.1016/j.cellsig.2011.05.004subject
Has Abstractpub_date
2011-10-01 00:00:00pages
1515-27issue
10eissn
0898-6568issn
1873-3913pii
S0898-6568(11)00141-0journal_volume
23pub_type
杂志文章,评审abstract：:Persistent exposure to ambient fine particulate matter (PM2.5) can exacerbate allergic diseases in humans. Mast cells play an important role in allergic inflammation in peripheral tissues, such as skin, mucosa, and lung. Engagement of the high-affinity Fc receptor leads to mast cell degranulation, releasing a variety ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2019.01.010
更新日期：2019-05-01 00:00:00
abstract：:Analysis of the genomic sequences, cDNAs and expressed sequence tags (ESTs) in human and mouse for the 12 genes of the gamma subunits of the heterotrimeric G proteins has allowed us to identify the common versus unique elements of the organization and expression of the members of this important gene family. All of the...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2005.04.011
更新日期：2006-02-01 00:00:00
abstract：:Proteoglycans (PGs) represent a large proportion of the components that constitute the extracellular matrix (ECM). They are a diverse group of glycoproteins characterized by a covalent link to a specific glycosaminoglycan type. As part of the ECM, heparan sulfate (HS)PGs participate in both physiological and pathologi...
journal_title：Cellular signalling
pub_type： 杂志文章,评审
doi：10.1016/j.cellsig.2020.109822
更新日期：2021-01-01 00:00:00
abstract：:Unc119 is an adapter signaling molecule, which regulates activation of tyrosine kinases in T cells, eosinophils and fibroblasts. It plays an important role in the photoreceptor synapses of the retina. Recently, we have shown that it inhibits bacterial uptake through macropinocytosis. In this paper we demonstrate a rol...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2009.09.022
更新日期：2010-01-01 00:00:00
abstract：:Endothelial cell activation by proinflammatory stimuli drives leukocyte recruitment through enhanced expression of counter-receptors such as vascular cell adhesion molecule-1 (VCAM-1). We previously demonstrated that activation of the receptor tyrosine kinase EphA2 with its ligand ephrin-A1 induces VCAM-1 expression. ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2018.05.008
更新日期：2018-09-01 00:00:00
abstract：:Extracellular adenine dinucleotides are modulators of blood vessel tone. We have previously demonstrated that Ap(2)A and Ap(4)A induce the synthesis of nitric oxide (NO) from bovine aortic endothelial cells (BAEC) while Ap(3)A and Ap(5)A do not [FEBS Lett. 427 (1998) 320; Arch. Biochem. Biophys. 364 (1999) 280.]. In t...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/s0898-6568(00)00147-9
更新日期：2001-02-01 00:00:00
abstract：:The induction of cytolytic activity in PC60, a murine T-cell hybridoma, is paralleled by a rise in the level of BLT-esterase (N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl esterase), a serine esterase specific for activated T-cells. Both interleukin-1 (IL-1) and dibutyryl cAMP were albe to increase the esterase activi...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/0898-6568(90)90045-c
更新日期：1990-01-01 00:00:00
abstract：:Pancreatic fibrosis, a key feature of chronic pancreatitis and pancreatic cancer, is mediated by activated pancreatic stellate cells (PSC). Connective tissue growth factor (CTGF) has been suggested to play a major role in fibrogenesis by enhancing PSC activation after binding to alpha5beta1 integrin. Here, we have foc...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2008.06.016
更新日期：2008-10-01 00:00:00
abstract：:Netrin-1 attracts or repels growing axons during development. The UNC5 receptors mediate the repulsive response, either alone or in complex with DCC receptors. The signaling mechanisms activated by UNC5 are poorly understood. Here, we examined the role of Rho GTPases in UNC5a signaling. We found that UNC5a induced neu...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2009.09.004
更新日期：2009-12-01 00:00:00
abstract：:The induction of suppressor of cytokine signalling (SOCS)3 expression context dependently involves regulation of SOCS3 transcript stability as previously demonstrated for MAPK activated protein kinase (MK)2-dependent regulation of SOCS3 expression by TNFα (Ehlting et al., 2007). In how far the IL-6-type cytokine OSM, ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2014.12.016
更新日期：2015-03-01 00:00:00
abstract：:Circulating symmetric dimethylarginine (SDMA) is increased in patients with chronic kidney disease. SDMA is considered an inert metabolite, but because it can transported into cells, we studied the effect of SDMA on glomerular endothelial cells. SDMA suppressed VEGF-induced endothelial nitric oxide synthase (eNOS) pho...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2014.09.024
更新日期：2015-01-01 00:00:00
abstract：:JNK proteins are conserved stress-activated MAP kinases. In C. elegans, the JNK-homolog KGB-1 plays essential roles in protection from heavy metals and protein folding stress. However, the contributions of KGB-1 are age-dependent, providing protection in larvae, but reducing stress resistance and shortening lifespan i...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2016.11.010
更新日期：2017-01-01 00:00:00
abstract：:Epidermal growth factor (EGF) and transforming growth factor type beta1 (TGF-beta1) exert opposite effects in most cells. A potential regulation between the two factors has been studied at a transcriptional level, but never at a protein level. MDA-MB-231 is a breast carcinoma cell line which possesses large quantities...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/s0898-6568(99)00048-0
更新日期：1999-10-01 00:00:00
abstract：:Cellular hypoxia can lead to cell death or adaptation and has important effects on development, physiology, and pathology. Here, we investigated the role and regulation of ceramide in hypoxia-induced apoptosis of SH-SY5Y neuroblastoma cells. Hypoxia increased the ceramide concentration; subsequently, we observed bioch...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2009.11.015
更新日期：2010-04-01 00:00:00
abstract：:Proliferation of cells under hypoxia is facilitated by metabolic adaptation, mediated by the transcriptional activator Hypoxia Inducible Factor-1 (HIF-1). HIF-1α, the inducible subunit of HIF-1 is regulated by oxygen as well as by oxygen-independent mechanisms involving phosphorylation. We have previously shown that C...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2015.02.017
更新日期：2015-06-01 00:00:00
abstract：:Signaling co-receptors are diverse, multifunctional components of most major signaling pathways, with roles in mediating and regulating signaling in both physiological and pathophysiological circumstances. Many of these signaling co-receptors, including CD44, glypicans, neuropilins, syndecans and TssRIII/betaglycan ar...
journal_title：Cellular signalling
pub_type： 杂志文章,评审
doi：10.1016/j.cellsig.2009.05.001
更新日期：2009-11-01 00:00:00
abstract：:Formycin A (1.0 mM) caused a rapid, sustained and rapidly reversible inhibition of effluent radioactivity in rat pancreatic islets prelabelled with myo-[2-3H]inositol and perifused in the presence of 8.3 mM D-glucose. This coincided with a progressive decrease in islet ATP content and transient inhibition of insulin r...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/0898-6568(95)02009-8
更新日期：1995-11-01 00:00:00
abstract：:Previous studies from acutely transfected HeLa cells have identified an acidic alpha-helix in the Type IIbeta PtdIns5P 4-kinase (PIPkin IIbeta) as a putative novel nuclear localisation sequence (Ciruela et al. Biochem. J. 364, 587-591 2000). However, some heterogeneity in cellular localisation was always observed, and...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2007.01.010
更新日期：2007-06-01 00:00:00
abstract：:Perivascular adipocyte (PVAC) biofunctions were closely related to cardiovascular diseases; its specific biological mechanisms remained unclear. How to adjust PVAC functions of vascular cells is an important topic. The present study was designed to investigate whether FAK/Pyk2 and ERK1/2 MAPK signaling pathways partic...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2014.09.017
更新日期：2014-12-01 00:00:00
abstract：:We have characterized the role of Drosophila PI3K and AKT in ERK pathway activation involving insulin-induced proliferation using Drosophila Schneider cells. After insulin treatment, dPI3K and dAKT activities were both increased along with activation of the dERK pathway components dMEK and dERK. The insulin-induced ac...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2004.04.004
更新日期：2004-11-01 00:00:00
abstract：:CK1δ and CK1ε are unique in the casein kinase 1 family and play critical roles in a number of physiological intracellular pathways. In particular, these kinases are involved in composing the mammalian circadian clock by phosphorylating core clock proteins. Considering that CK1δ/ε phosphorylate other key biological mol...
journal_title：Cellular signalling
pub_type： 杂志文章,评审
doi：10.1016/j.cellsig.2016.12.010
更新日期：2017-02-01 00:00:00
abstract：:Suppressor of fused (SUFU) is an essential negative regulator of the mammalian Hedgehog (HH) signaling pathway and its loss is associated with cancer development. On a cellular level, endogenous SUFU can mainly be detected in the cytoplasm and the nucleus. However, immunostaining of pancreatic cancer specimen revealed...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2013.08.037
更新日期：2013-12-01 00:00:00
abstract：:Intracellular calcium signaling pathways play a major role in cellular responses such as proliferation, differentiation and apoptosis. Human embryonic stem cells (hESC) provide new possibilities to explore the development and differentiation of various cell types of the human body. Intracellular calcium responses to v...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2012.12.024
更新日期：2013-04-01 00:00:00
abstract：:We have investigated the role of the hydrolysis of glycosyl-phosphatidylinositol (GPI) as one of the signalling pathways elicited after interaction of epidermal growth factor (EGF) with its specific plasma membrane receptor (EGFR). Endogenous GPI was characterized in both NIH 3T3 mouse fibroblast cells and in EGFR-tra...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/0898-6568(95)00002-7
更新日期：1995-05-01 00:00:00
abstract：:Cross-talk between nuclear receptors involved in the control of drug metabolism is being increasingly recognised as a source of drug side effects. Omeprazole is a well known activator of the aryl hydrocarbon receptor (AhR). We investigated the regulation of AhR by omeprazole-sulphide, a degradation metabolite of omepr...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2005.07.007
更新日期：2006-05-01 00:00:00
abstract：:The possible involvement of zeta isozyme of protein kinase C (PKC zeta) in phorbol ester-induced signal transduction was investigated in mouse epidermal cells. Western blot analysis of RESOURCE Q column chromatography eluates obtained from 105,000 g supernatants and particulate fractions of epidermal cells was perform...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/0898-6568(95)00019-l
更新日期：1995-07-01 00:00:00
abstract：:The implication of protein kinase C in the phenomenon of pancreatic acinar cell desensitization to carbamylcholine, caerulein and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated using a potent PKC inhibitor, staurosporine. At a concentration of 1 microM, staurosporine caused a maximum 64%...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/0898-6568(91)90018-p
更新日期：1991-01-01 00:00:00
abstract：:Nur77 (NR4A1) plays an important role in various inflammatory responses. Nur77 is rapidly degraded in cells and its protein level is critically controlled. Although few E3 ligases regulating the Nur77 protein have been defined, the deubiquitinase (DUB) responsible for Nur77 stability has not been reported to date. We ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2019.03.018
更新日期：2019-07-01 00:00:00
abstract：:Mice lacking the gene for suppressor of cytokine signaling 1 (SOCS1) show defective homeostasis of T lymphocytes due to accumulation of CD8(+) T cells, resulting at least partly from dysregulated IL-15 signaling. IL-15 alone does not stimulate proliferation of naïve CD8 T cells, but can synergize with IL-21 to induce ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2006.10.003
更新日期：2007-04-01 00:00:00
abstract：:β-Arrestins are multifunctional adaptor proteins best know for their vital role in regulating G protein coupled receptor (GPCR) trafficking and signaling. β-arrestin2 recruitment and receptor internalization of corticotropin-releasing factor receptor 1 (CRFR1), a GPCR whose antagonists have been shown to demonstrate b...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2019.109361
更新日期：2019-11-01 00:00:00
