Akt/PKB: one kinase, many modifications

2015 ◽  
Vol 468 (2) ◽  
pp. 203-214 ◽  
Author(s):  
Guillermo Risso ◽  
Matías Blaustein ◽  
Berta Pozzi ◽  
Pablo Mammi ◽  
Anabella Srebrow
Keyword(s):  
Large Body ◽  
Fine Tuning ◽  
Serine Threonine Kinase ◽  
Post Translational Modifications ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Extracellular Signals ◽  
Signalling Molecule

Akt/PKB, a serine/threonine kinase member of the AGC family of proteins, is involved in the regulation of a plethora of cellular processes triggered by a wide diversity of extracellular signals and is thus considered a key signalling molecule in higher eukaryotes. Deregulation of Akt signalling is associated with a variety of human diseases, revealing Akt-dependent pathways as an attractive target for therapeutic intervention. Since its discovery in the early 1990s, a large body of work has focused on Akt phosphorylation of two residues, Thr308 and Ser473, and modification of these two sites has been established as being equivalent to Akt activation. More recently, Akt has been identified as a substrate for many different post-translational modifications, including not only phosphorylation of other residues, but also acetylation, glycosylation, oxidation, ubiquitination and SUMOylation. These modifications could provide additional regulatory steps for fine-tuning Akt function, Akt trafficking within the cell and/or for determining the substrate specificity of this signalling molecule. In the present review, we provide an overview of these different post-translational modifications identified for Akt, focusing on their consequences for this kinase activity.

scholarly journals Effects of apigenin, lycopene and astaxanthin on 7β-hydroxycholesterol-induced apoptosis and Akt phosphorylation in U937 cells

2008 ◽  
Vol 100 (2) ◽  
pp. 287-296 ◽  
Author(s):  
Sinéad Lordan ◽  
Cora O'Neill ◽  
Nora M. O'Brien
Keyword(s):  
Cell Death ◽  
Cell Viability ◽  
U937 Cells ◽  
Caspase Activation ◽  
Serine Threonine Kinase ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Threonine Kinase ◽  
Low Concentrations ◽  
Induced Apoptosis

Oxysterols arise from the enzymic or non-enzymic oxidation of cholesterol and have been shown to be cytotoxic to certain cell lines. In particular, apoptosis induced by the oxysterol 7β-hydroxycholesterol (7β-OH) has been associated with the generation of oxidative stress, cytochrome c release and caspase activation. Due to the fundamental importance of apoptosis in pathological processes, the identification of substances capable of modulating this form of cell death is now actively researched. The objective of the present study was to investigate if apigenin, lycopene and astaxanthin could inhibit 7β-OH-induced apoptosis in U937 cells. Pretreatment with 0·1 μm-astaxanthin protected against apoptosis, while lycopene did not oppose the adverse effects of 7β-OH. At low concentrations, apigenin did not protect against oxysterol-induced apoptosis; however, at higher concentrations it intensified cell death. Additionally, we investigated the effect of 7β-OH, apigenin and astaxanthin on the activation of the serine threonine kinase Akt (phosphorylated Akt:Akt ratio) to determine whether the effect on cell viability and growth was linked to the Akt signalling pathway. Akt activation was decreased in the oxysterol-treated cells compared with control cells; however, this did not attain significance. Interestingly, activation of Akt was significantly reduced compared with control cells following incubation with apigenin and astaxanthin both in the absence and in the presence of 7β-OH. Our data suggest that apigenin, lycopene and astaxanthin failed to protect against 7β-OH-induced apoptosis, and the decrease in cell viability and the increase in apoptotic nuclei induced by the antioxidants appear to be associated with down regulation of Akt activity.

GSK-3 Inhibitors in Regulation and Controlling of Colon Carcinoma

2021 ◽  
Vol 22 ◽  
Author(s):  
Sitansu Sekhar Nanda ◽  
Md Imran Hossain ◽  
Heongkyu Ju ◽  
Dong Kee Yi
Keyword(s):  
Colon Carcinoma ◽  
Clinical Studies ◽  
Glycogen Synthesis ◽  
Morphological Examination ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Adenocarcinoma Cells ◽  
Membrane Bound

Background: GSK-3 inhibitors became a novel therapeutic agent treating cancer. There are so many uses of GSK-3 inhibitor for treating cancer like breast cancer, lung cancer, gastric cancer, and no pathological changes are shown by the morphological examination of GSK-3. Objectives: This review describes the recent affairs using GSK-3 inhibitors, mainly treating in colon carcinoma. The authorsAuthors have also shown the different mechanisms of different GSK-3 inhibitors for treating various cancers and proposed some mechanisms that can be useful for further research by GSK-3 inhibitors for various cancerscancer including colon carcinoma. Results: The majority of the cancers and pre-cancerous lesions are stimulated by the transformation of membrane-bound arachidonic acid (AA) to eicosanoids for the viability, proliferation, and spread of cancer. GSK-3 inhibitors can reinstate hostility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) responsiveness in gastric adenocarcinoma cells. GSK-3, the final enzyme in glycogen synthesis, is a serine/threonine kinase that phosphorylates varied sequences that are more than a hundred in number, within proteins in an array of heterogeneous pathways. It is an essential module of an exceptionally huge number of cellular processes, a fundamental role in many metabolic processes and diseases. Many patients achieve long term remission with outstanding survival diagnosed with colon cancer through it. Conclusion: Before the extensive application of these proposed mechanisms of GSK-3 inhibitor, further evaluation and clinical studies are needed. After doing the appropriate clinical studies and morphological examination, it can be appropriate for extensive application.

scholarly journals Tyrosine phosphorylation of the scaffold protein IQGAP1 in the MET pathway alters function

2020 ◽  
Vol 295 (52) ◽  
pp. 18105-18121
Author(s):  
Andrew C. Hedman ◽  
Dean E. McNulty ◽  
Zhigang Li ◽  
Laëtitia Gorisse ◽  
Roland S. Annan ◽  
...  
Keyword(s):  
Cell Function ◽  
Scaffold Protein ◽  
Site Directed Mutagenesis ◽  
Human Lung Cancer ◽  
Post Translational Modifications ◽  
Akt Activation ◽  
Cellular Processes ◽  
Src Signaling ◽  
Chemical Inhibitors ◽  
Hepatocyte Growth

IQGAP1 is a key scaffold protein that regulates numerous cellular processes and signaling pathways. Analogous to many other cellular proteins, IQGAP1 undergoes post-translational modifications, including phosphorylation. Nevertheless, very little is known about the specific sites of phosphorylation or the effects on IQGAP1 function. Here, using several approaches, including MS, site-directed mutagenesis, siRNA-mediated gene silencing, and chemical inhibitors, we identified the specific tyrosine residues that are phosphorylated on IQGAP1 and evaluated the effect on function. Tyr-172, Tyr-654, Tyr-855, and Tyr-1510 were phosphorylated on IQGAP1 when phosphotyrosine phosphatase activity was inhibited in cells. IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET. To investigate the biological sequelae of phosphorylation, we generated a nonphosphorylatable IQGAP1 construct by replacing Tyr-1510 with alanine. The ability of hepatocyte growth factor, the ligand for MET, to promote AKT activation and cell migration was significantly greater when IQGAP1-null cells were reconstituted with IQGAP1 Y1510A than when cells were reconstituted with WT IQGAP1. Collectively, our data suggest that phosphorylation of Tyr-1510 of IQGAP1 alters cell function. Because increased MET signaling is implicated in the development and progression of several types of carcinoma, IQGAP1 may be a potential therapeutic target in selected malignancies.

scholarly journals Relevance of STK11 Mutations Regarding Immune Cell Infiltration, Drug Sensitivity, and Cellular Processes in Lung Adenocarcinoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Zhenqing Li ◽  
Bo Ding ◽  
Jianxun Xu ◽  
Kai Mao ◽  
Pengfei Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Drug Sensitivity ◽  
Immune Cell ◽  
Differentially Expressed ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Wild Type ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cellular Processes

Serine/threonine kinase 11 (STK11) is one member of the serine/threonine kinase family, which is involved in regulating cell polarity, apoptosis, and DNA damage repair. In lung adenocarcinoma (LUAD), it can play as one tumor suppressor and always be mutated. In this study, we aimed to assess the relevance of STK11 mutations in LUAD, in which we also studied the correlation among immune cell infiltration, drug sensitivity, and cellular processes. By performing the bioinformatics analysis of the Cancer Genome Atlas (TCGA) about LUAD patients, we found that the mutation efficiency of STK11 mutations is about 19%. Additionally, the differentially expressed gene analysis showed that there were 746 differentially expressed genes (DEGs) between LUAD patients with and without STK11 mutations. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis showed that the DEGs were enriched in various tumorigenesis signaling pathways and metabolic processes. Among these DEGs, the top ranking 21 genes were found that they were more frequently mutated in the STK11 mutation group than in the wild-type group (p-value<0.01). Finally, the LUAD patients with STK11 mutations suffered the worse immune cell infiltration levels than the LUAD patients with wild-type. The STK11 gene copy number was correlated with immune cell infiltration. Aiming to develop the therapeutic drugs, we performed Genomics of Drug Sensitivity in Cancer (GDSC) data to identify the potential therapeutic candidate and the results showed that Nutlin-3a(-) may be a sensitive drug for LUAD cases harboring STK11 mutations. The specific genes and pathways shown to be associated with LUAD cases involving STK11 mutations may serve as targets for individualized LUAD treatment.

scholarly journals Lanthionine synthetase C–like protein 2 (LanCL2) is a novel regulator of Akt

2014 ◽  
Vol 25 (24) ◽  
pp. 3954-3961 ◽  
Author(s):  
Min Zeng ◽  
Wilfred A. van der Donk ◽  
Jie Chen
Keyword(s):  
Insulin Receptor ◽  
Insulin Receptor Substrate ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Cellular Processes ◽  
Human Liver Cells ◽  
Wide Range ◽  
Physical Interactions ◽  
Protein Kinase Akt

The serine/threonine protein kinase Akt controls a wide range of biochemical and cellular processes under the modulation of a variety of regulators. In this study, we identify the lanthionine synthetase C–like 2 (LanCL2) protein as a positive regulator of Akt activation in human liver cells. LanCL2 knockdown dampens serum- and insulin-stimulated Akt phosphorylation, whereas LanCL2 overexpression enhances these processes. Neither insulin receptor phosphorylation nor the interaction between insulin receptor substrate and phosphatidylinositide 3-kinase (PI3K) is affected by LanCL2 knockdown. LanCL2 also does not function through PP2A, a phosphatase of Akt. Instead, LanCL2 directly interacts with Akt, with a preference for inactive Akt. Moreover, we show that LanCL2 also binds to the Akt kinase mTORC2, but not phosphoinositide-dependent kinase 1. Whereas LanCL2 is not required for the Akt-mTORC2 interaction, recombinant LanCL2 enhances Akt phosphorylation by target of rapamycin complex 2 (mTORC2) in vitro. Finally, consistent with a function of Akt in regulating cell survival, LanCL2 knockdown increases the rate of apoptosis, which is reversed by the expression of a constitutively active Akt. Taken together, our findings reveal LanCL2 as a novel regulator of Akt and suggest that LanCL2 facilitates optimal phosphorylation of Akt by mTORC2 via direct physical interactions with both the kinase and the substrate.

New insights into PKC family affairs: three novel phosphorylation sites in PKCϵ and at least one is regulated by PKCα

2008 ◽  
Vol 411 (2) ◽  
pp. e15-e16 ◽  
Author(s):  
Christer Larsson
Keyword(s):  
Phosphorylation Sites ◽  
Functional Importance ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Biochemical Journal ◽  
Pkc Isoforms ◽  
Evolutionarily Conserved ◽  
The Individual

PKCϵ (protein kinase Cϵ) is a serine/threonine kinase, and a member of the PKC family of isoforms. The different PKC isoforms regulate many cellular processes of importance for disease. It is therefore desirable to obtain tools to specifically modulate the activity of the individual isoforms and to develop markers of PKC activity. The paper by Durgan et al. in this issue of the Biochemical Journal has taken us some steps further towards these goals. In the paper they identify three previously unknown phosphorylation sites in PKCϵ. All of them are specific for the ϵ isoform, evolutionarily conserved and tightly regulated. The phosphorylation of one site is critical for the binding of PKCϵ to 14-3-3β, suggesting it is of functional importance. The results provide important novel findings that uncover new aspects of PKCϵ regulation and reveal new possibilities for detecting PKCϵ activity in situ.

scholarly journals Tyr198 is the Essential Autophosphorylation Site for STK16 Localization and Kinase Activity

2019 ◽  
Vol 20 (19) ◽  
pp. 4852 ◽  
Author(s):  
Junjun Wang ◽  
Juanjuan Liu ◽  
Xinmiao Ji ◽  
Xin Zhang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Kinase Domain ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Activation Segment ◽  
And Function

STK16, reported as a Golgi localized serine/threonine kinase, has been shown to participate in multiple cellular processes, including the TGF-β signaling pathway, TGN protein secretion and sorting, as well as cell cycle and Golgi assembly regulation. However, the mechanisms of the regulation of its kinase activity remain underexplored. It was known that STK16 is autophosphorylated at Thr185, Ser197, and Tyr198 of the activation segment in its kinase domain. We found that STK16 localizes to the cell membrane and the Golgi throughout the cell cycle, but mutations in the auto-phosphorylation sites not only alter its subcellular localization but also affect its kinase activity. In particular, the Tyr198 mutation alone significantly reduced the kinase activity of STK16, abolished its Golgi and membrane localization, and affected the cell cycle progression. This study demonstrates that a single site autophosphorylation of STK16 could affect its localization and function, which provides insights into the molecular regulatory mechanism of STK16’s kinase activity.

X-ray structural studies of the entire extracellular region of the serine/threonine kinase PrkC from Staphylococcus aureus

2011 ◽  
Vol 435 (1) ◽  
pp. 33-41 ◽  
Author(s):  
Alessia Ruggiero ◽  
Flavia Squeglia ◽  
Daniela Marasco ◽  
Roberta Marchetti ◽  
Antonio Molinaro ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Serine Threonine Kinase ◽  
X Ray ◽  
Threonine Kinase ◽  
Extracellular Milieu ◽  
Cellular Processes ◽  
Extracellular Region ◽  
High Concentrations ◽  
Growing Conditions ◽  
Adhesive Proteins

Bacterial serine/threonine kinases modulate a wide number of cellular processes. The serine/threonine kinase PrkC from the human pathogen Staphylococcus aureus was also shown to induce germination of Bacillus subtilis spores, in response to cell wall muropeptides. The presence of muropeptides in the bacterial extracellular milieu is a strong signal that the growing conditions are promising. In the present paper, we report the X-ray structure of the entire extracellular region of PrkC from S. aureus. This structure reveals that the extracellular region of PrkC, EC-PrkC, is a linear modular structure composed of three PASTA (penicillin binding-associated and serine/threonine kinase-associated) domains and an unpredicted C-terminal domain, which presents the typical features of adhesive proteins. Using several solution techniques, we also found that EC-PrkC shows no tendency to dimerize even in the presence of high concentrations of muropeptides. X-ray structural results obtained in the present study provide molecular clues into the mechanism of muropeptide-induced PrkC activation.

scholarly journals Serine/threonine kinase akt activation regulates the activity of retinal serine/threonine phosphatases, PHLPP and PHLPPL

2010 ◽  
Vol 113 (2) ◽  
pp. 477-488 ◽  
Author(s):  
Yogita Kanan ◽  
Hiroyuki Matsumoto ◽  
Hongman Song ◽  
Maxim Sokolov ◽  
Robert E. Anderson ◽  
...  
Keyword(s):  
Serine Threonine Kinase ◽  
Akt Activation ◽  
Threonine Kinase

Involvement of PKCe in the Negative Regulation of Akt Activation Stimulated by G-CSF.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2187-2187
Author(s):  
Hong Liu ◽  
Fan Dong
Keyword(s):  
Molecular Mechanisms ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Signaling Cascades ◽  
Granulocytic Differentiation ◽  
Serine Threonine Kinase ◽  
Akt Activation ◽  
Threonine Kinase ◽  
Receptor Mutant

Abstract Granulocyte colony-stimulating factor (G-CSF) supports the proliferation, differentiation and survival of myeloid cells by stimulating the activation of several signaling cascades including the serine/threonine kinase Akt pathway. Akt activation has been shown to be important for G-CSF-induced survival and granulocytic differentiation. Although significant progresses have been made in our understanding of the molecular mechanisms by which Akt is activated, much less is known about the signaling events that negatively regulate Akt activation. Interestingly, G-CSF-induced activation of Akt was completely inhibited when myeloid 32D cells transfected with the wild type G-CSF receptor were incubated with phorbol-12-myristate 13-acetate (PMA), a PKC activator. PMA-mediated inhibition of Akt activation occurred with 5 min and lasted at least 1 hour. Previously, it has been shown that a carboxyl terminally truncated G-CSF receptor (D715), whose expression is associated with the development of acute myeloid leukemia in patients with severe congenital neutropenia (SCN), mediates significantly prolonged Akt activation. Notably, Akt activation by G-CSF in 32D cells expressing the D715 receptor mutant was rapidly downregulated by PMA treatment. The inhibitory effect of PMA on Akt activation was abolished by pretreatment of cells with the specific PKC inhibitor GF109203X, suggesting that PKC-dependent pathway negatively regulates Akt activation. Ro-31-7549, a specific inhibitor of PKCe, also abrogated PMA-mediated inhibition of Akt activation whereas rottlerin and Go6976, inhibitors of PKCd and PKC a/bI,, respectively, displayed no effect. Together, these results identified PKCe as being critically involved in PMA-mediated inhibition of Akt activation. Experiments are currently under way to determine the mechanism by which PKCe downregulates Akt activation and the role of PKCe in the regulation of cell proliferation, differentiation and survival in response to G-CSF.

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