scholarly journals PRMT5-mediated arginine methylation activates AKT kinase to govern tumorigenesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shasha Yin ◽  
Liu Liu ◽  
Charles Brobbey ◽  
Viswanathan Palanisamy ◽  
Lauren E. Ball ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Arginine Methylation ◽  
Akt Signaling Pathway ◽  
Akt Inhibitor ◽  
Akt Kinase ◽  
Akt Activation ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
Subsequent Activation ◽  
Oncogenic Function

AbstractAKT is involved in a number of key cellular processes including cell proliferation, apoptosis and metabolism. Hyperactivation of AKT is associated with many pathological conditions, particularly cancers. Emerging evidence indicates that arginine methylation is involved in modulating AKT signaling pathway. However, whether and how arginine methylation directly regulates AKT kinase activity remain unknown. Here we report that protein arginine methyltransferase 5 (PRMT5), but not other PRMTs, promotes AKT activation by catalyzing symmetric dimethylation of AKT1 at arginine 391 (R391). Mechanistically, AKT1-R391 methylation cooperates with phosphatidylinositol 3,4,5 trisphosphate (PIP3) to relieve the pleckstrin homology (PH)-in conformation, leading to AKT1 membrane translocation and subsequent activation by phosphoinositide-dependent kinase-1 (PDK1) and the mechanistic target of rapamycin complex 2 (mTORC2). As a result, deficiency in AKT1-R391 methylation significantly suppresses AKT1 kinase activity and tumorigenesis. Lastly, we show that PRMT5 inhibitor synergizes with AKT inhibitor or chemotherapeutic drugs to enhance cell death. Altogether, our study suggests that R391 methylation is an important step for AKT activation and its oncogenic function.

scholarly journals Nuclear Functions of the Tyrosine Kinase Src

2020 ◽  
Vol 21 (8) ◽  
pp. 2675 ◽  
Author(s):  
Giulia Bagnato ◽  
Martina Leopizzi ◽  
Enrica Urciuoli ◽  
Barbara Peruzzi
Keyword(s):  
Plasma Membrane ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Src Family Kinases ◽  
Main Function ◽  
Nuclear Compartment ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
Representative Member

Src is the representative member of the Src-family kinases (SFKs), a group of tyrosine kinases involved in several cellular processes. Its main function has been for long confined to the plasma membrane/cytoplasm compartment, being a myristoylated protein anchored to the cell membrane and functioning downstream to receptors, most of them lacking intrinsic kinase activity. In the last decades, new roles for some SFKs have been described in the nuclear compartment, suggesting that these proteins can also be involved in directly regulating gene transcription or nucleoskeleton architecture. In this review, we focused on those nuclear functions specifically attributable to Src, by considering its function as both tyrosine kinase and adapting molecule. In particular, we addressed the Src involvement in physiological as well as in pathological conditions, especially in tumors.

scholarly journals Akt2, a Novel Functional Link between p38 Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase Pathways in Myogenesis

2004 ◽  
Vol 24 (9) ◽  
pp. 3607-3622 ◽  
Author(s):  
Ivelisse Gonzalez ◽  
Gyanendra Tripathi ◽  
Emma J. Carter ◽  
Laura J. Cobb ◽  
Dervis A. M. Salih ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Kinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Myoblast Differentiation ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Kinase ◽  
Akt Activation ◽  
Protein Levels ◽  
Mitogen Activated Protein

ABSTRACT Activation of either the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt or the p38 mitogen-activated protein kinase (MAPK) signaling pathways accelerates myogenesis but only when the reciprocal pathway is functional. We therefore examined the hypothesis that cross-activation between these signaling cascades occurs to orchestrate myogenesis. We reveal a novel and reciprocal cross-talk and activation between the PI 3-kinase/Akt and p38 MAPK pathways that is essential for efficient myoblast differentiation. During myoblast differentiation, Akt kinase activity correlated with S473 but not T308 phosphorylation and occurred 24 h after p38 activation. Inhibition or activation of p38 with SB203580, dominant-negative p38, or MKK6EE regulated Akt kinase activity. Analysis of Akt isoforms revealed a specific increase in Akt2 protein levels that coincided with AktS473 phosphorylation during myogenesis and an enrichment of S473-phosphorylated Akt2. Akt2 promoter activity and protein levels were regulated by p38 activation, thus providing a mechanism for communication. Subsequent Akt activation by S473 phosphorylation was PI 3-kinase dependent and specific for Akt2 rather than Akt1. Complementary to p38-mediated transactivation of Akt, activation or inhibition of PI 3-kinase regulated p38 activity upstream of MKK6, demonstrating reciprocal communication and positive feedback characteristic of myogenic regulation. Our findings have identified novel communication between p38 MAPK and PI 3-kinase/Akt via Akt2.

scholarly journals Roles of Microglial Ion Channel in Neurodegenerative Diseases

2021 ◽  
Vol 10 (6) ◽  
pp. 1239
Author(s):  
Alexandru Cojocaru ◽  
Emilia Burada ◽  
Adrian-Tudor Bălșeanu ◽  
Alexandru-Florian Deftu ◽  
Bogdan Cătălin ◽  
...  
Keyword(s):  
Ion Channels ◽  
Neurodegenerative Diseases ◽  
Excitable Cells ◽  
Proton Channels ◽  
Voltage Gated ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
The Common ◽  
Transient Receptor ◽  
The Impact

As the average age and life expectancy increases, the incidence of both acute and chronic central nervous system (CNS) pathologies will increase. Understanding mechanisms underlying neuroinflammation as the common feature of any neurodegenerative pathology, we can exploit the pharmacology of cell specific ion channels to improve the outcome of many CNS diseases. As the main cellular player of neuroinflammation, microglia play a central role in this process. Although microglia are considered non-excitable cells, they express a variety of ion channels under both physiological and pathological conditions that seem to be involved in a plethora of cellular processes. Here, we discuss the impact of modulating microglia voltage-gated, potential transient receptor, chloride and proton channels on microglial proliferation, migration, and phagocytosis in neurodegenerative diseases.

scholarly journals Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice

2000 ◽  
Vol 167 (1) ◽  
pp. 107-115 ◽  
Author(s):  
J Shao ◽  
H Yamashita ◽  
L Qiao ◽  
JE Friedman
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Transporter ◽  
Kinase Activity ◽  
Glycogen Synthase ◽  
Glut4 Translocation ◽  
Akt Kinase ◽  
Insulin Signal Transduction ◽  
Kinase Pathway

Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/KsJ-Lepr(db/db) mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85alpha, or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0.05) in both tissues from db/db mice. Insulin increased Akt-Ser(473) phosphorylation by two- to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser(473) phosphorylation was decreased by 32% (P<0.05) and 69% (P<0.05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0.05). The level of insulin-stimulated tyrosine phosphorylation of p85alpha from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0.05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.

scholarly journals The Role of Prokineticin 2 in Oxidative Stress and in Neuropathological Processes

2021 ◽  
Vol 12 ◽  
Author(s):  
Roberta Lattanzi ◽  
Cinzia Severini ◽  
Daniela Maftei ◽  
Luciano Saso ◽  
Aldo Badiani
Keyword(s):  
Pain Perception ◽  
G Protein Coupled Receptors ◽  
Cellular Processes ◽  
Prokineticin 2 ◽  
Physiological Processes ◽  
Pathological Conditions ◽  
Double Function ◽  
The Central Nervous System ◽  
G Protein Coupled

The prokineticin (PK) family, prokineticin 1 and Bv8/prokineticin 2 (PROK2), initially discovered as regulators of gastrointestinal motility, interacts with two G protein-coupled receptors, PKR1 and PKR2, regulating important biological functions such as circadian rhythms, metabolism, angiogenesis, neurogenesis, muscle contractility, hematopoiesis, immune response, reproduction and pain perception. PROK2 and PK receptors, in particular PKR2, are widespread distributed in the central nervous system, in both neurons and glial cells. The PROK2 expression levels can be increased by a series of pathological insults, such as hypoxia, reactive oxygen species, beta amyloid and excitotoxic glutamate. This suggests that the PK system, participating in different cellular processes that cause neuronal death, can be a key mediator in neurological/neurodegenerative diseases. While many PROK2/PKRs effects in physiological processes have been documented, their role in neuropathological conditions is not fully clarified, since PROK2 can have a double function in the mechanisms underlying to neurodegeneration or neuroprotection. Here, we briefly outline the latest findings on the modulation of PROK2 and its cognate receptors following different pathological insults, providing information about their opposite neurotoxic and neuroprotective role in different pathological conditions.

scholarly journals WDFY2 potentiates hepatic insulin sensitivity and controls endosomal localization of the insulin receptor and IRS1/2

2020 ◽  
Author(s):  
Ada Admin ◽  
Luyao Zhang ◽  
Xue Li ◽  
Nan Zhang ◽  
Xin Yang ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Akt Signaling Pathway ◽  
Insulin Stimulation ◽  
Glycogen Accumulation ◽  
Metabolic Defects ◽  
Insulin Receptor Substrates ◽  
Systemic Insulin Resistance ◽  
Important Regulator ◽  
Subsequent Activation ◽  
Gsk 3Β

Endosomes help activate the hepatic insulin-evoked Akt signaling pathway, but the underlying regulatory mechanisms are unclear. Previous studies have suggested that the endosome located protein WD Repeat and FYVE Domain Containing 2 (WDFY2) might be involved in metabolic disorders, such as diabetes. Here, we generated <i>Wdfy2</i> knockout (KO) mice and assessed the metabolic consequences. These KO mice exhibited systemic insulin resistance, with increased gluconeogenesis and suppressed glycogen accumulation in the liver. Mechanistically, we found that the insulin-stimulated activation of Akt2 and its substrates FoxO1 and GSK-3β, is attenuated in the <i>Wdfy2</i> KO liver and H2.35 hepatocytes, suggesting that WDFY2 acts as an important regulator of hepatic Akt2 signaling. We further found that WDFY2 interacts with the insulin receptor (INSR) via its WD1-4 domain and localizes the INSR to endosomes after insulin stimulation. This process ensures that the downstream insulin receptor substrates 1 and 2 (IRS1/2) can be recruited to the endosomal INSR. IRS1/2–INSR binding promotes IRS1/2 phosphorylation and subsequent activation, initiating downstream Akt2 signaling in the liver. Interestingly, adeno-associated viral WDFY2 delivery ameliorated metabolic defects in <i>db/db</i> mice. These findings demonstrate that WDFY2 activates insulin-evoked Akt2 signaling by controlling endosomal localization of the insulin receptor and IRS1/2 in hepatocytes. This pathway might constitute a new potential target for diabetes prevention and/or treatment.

scholarly journals CDK10 in Gastrointestinal Cancers: Dual Roles as a Tumor Suppressor and Oncogene

2021 ◽  
Vol 11 ◽  
Author(s):  
Zainab A. Bazzi ◽  
Isabella T. Tai
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Kinase Activity ◽  
Screening Assay ◽  
Cellular Processes ◽  
Molecule Inhibitor ◽  
High Throughput Screening Assay ◽  
Kinase Activity Assay

Cyclin-dependent kinase 10 (CDK10) is a CDC2-related serine/threonine kinase involved in cellular processes including cell proliferation, transcription regulation and cell cycle regulation. CDK10 has been identified as both a candidate tumor suppressor in hepatocellular carcinoma, biliary tract cancers and gastric cancer, and a candidate oncogene in colorectal cancer (CRC). CDK10 has been shown to be specifically involved in modulating cancer cell proliferation, motility and chemosensitivity. Specifically, in CRC, it may represent a viable biomarker and target for chemoresistance. The development of therapeutics targeting CDK10 has been hindered by lack a specific small molecule inhibitor for CDK10 kinase activity, due to a lack of a high throughput screening assay. Recently, a novel CDK10 kinase activity assay has been developed, which will aid in the development of small molecule inhibitors targeting CDK10 activity. Discovery of a small molecular inhibitor for CDK10 would facilitate further exploration of its biological functions and affirm its candidacy as a therapeutic target, specifically for CRC.

Abstract 16: BcrKinase is a Novel Akt Kinase That Modulates Scavenger Receptor BI- and PDZK1-dependent Actions of HDL in Endothelium

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Anastasia Sacharidou ◽  
Wan-Ru Lee ◽  
Philip E Shaul ◽  
Chieko Mineo
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Kinase Activity ◽  
Scavenger Receptor ◽  
Adaptor Protein ◽  
Myelogenous Leukemia ◽  
Endothelial Cell Migration ◽  
Kinase Assay ◽  
Type I ◽  
Akt Kinase

High density lipoprotein cholesterol (HDL) has direct atheroprotective actions on endothelium. These are mediated by scavenger receptor class B, type I (SR-BI) and its adaptor protein PDZK1, and they entail the activation of Akt kinase, which phosphorylates and thereby stimulates endothelial nitric oxide synthase (eNOS). In the present work we sought to determine how PDZK1 couples HDL/SR-BI to Akt and eNOS to modulate endothelial function. Using tandem affinity purification (TAP) following the infection of the human endothelial cell line EAhy926 with adenovirus expressing TAP-tagged PDZK1, we identified Breakpoint Cluster Region (Bcr) kinase as a PDZK1 interacting protein in endothelium. Whereas Bcr is well-known as a component of the Bcr-Abl fusion protein that results from translocation of the Philadelphia chromosome in chronic myelogenous leukemia, little is known of its function in endothelial cells. Bcr contains several distinctive domains including a C-terminal PDZ binding motif and a serine/threonine protein kinase domain. In primary human aortic endothelial cells (HAEC), we determined that endogenous Bcr interacts with PDZK1 in an HDL-dependent manner, and that Bcr is required for HDL-induced activation of eNOS and HDL stimulation of endothelial cell migration, which underlies the ability of the lipoprotein to promote endothelial monolayer integrity. Studies of mutant forms of Bcr with disruption of PDZK1 binding or kinase activity introduced into endothelial cells further revealed that Bcr-PDZK1 interaction and its kinase function are required for HDL activation of Akt and eNOS. Using a novel kinase assay that we recently developed that employs time-resolved Forster resonance energy transfer, we found that via SR-BI and PDZK1, HDL stimulates Bcr kinase activity in endothelial cells more than 20-fold. In addition, using Akt-based peptides in studies of the two known kinases for Akt, mTOR and PDK1, we determined that HDL activates Bcr kinase to directly phosphorylate Akt-Ser473 in an mTOR independent manner, and that Akt-Thr308 is a direct substrate of PDK1. These collective findings have identified Bcr to be a novel kinase for Akt, and they have revealed that Bcr is critically involved in HDL modulation of endothelial cell phenotype.

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 Alternative signaling pathways from IGF1 or insulin to AKT activation and FOXO1 nuclear efflux in adult skeletal muscle fibers

2020 ◽  
Vol 295 (45) ◽  
pp. 15292-15306
Author(s):  
Sarah J. Russell ◽  
Martin F. Schneider
Keyword(s):  
Muscle Atrophy ◽  
Kinase Inhibitors ◽  
Muscle Fibers ◽  
Therapeutic Interventions ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Inhibitor ◽  
Promoting Effect ◽  
Adult Skeletal Muscle ◽  
Akt Activation ◽  
Phosphatidylinositol 3

Muscle atrophy is regulated by the balance between protein degradation and synthesis. FOXO1, a transcription factor, helps to determine this balance by activating pro-atrophic gene transcription when present in muscle fiber nuclei. Foxo1 nuclear efflux is promoted by AKT-mediated Foxo1 phosphorylation, eliminating FOXO1's atrophy-promoting effect. AKT activation can be promoted by insulin-like growth factor 1 (IGF1) or insulin via a pathway including IGF1 or insulin, phosphatidylinositol 3-kinase, and AKT. We used confocal fluorescence time-lapse imaging of FOXO1–GFP in adult isolated living muscle fibers maintained in culture to explore the effects of IGF1 and insulin on FOXO1–GFP nuclear efflux with and without pharmacological inhibitors. We observed that although AKT inhibitor blocks the IGF1- or insulin-induced effect on FOXO1 nuclear efflux, phosphatidylinositol 3-kinase inhibitors, which we show to be effective in these fibers, do not. We also found that inhibition of the protein kinase ACK1 or ATM contributes to the suppression of FOXO1 nuclear efflux after IGF1. These results indicate a novel pathway that has been unexplored in the IGF1- or insulin-induced regulation of FOXO1 and present information useful both for therapeutic interventions for muscle atrophy and for further investigative areas into insulin insensitivity and type 2 diabetes.

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