scholarly journals Control Of Phosphoinositide Synthesis And Degradation By The Acyltransferase Lycat

2021 ◽  
Author(s):  
Yasmin Awadeh
Keyword(s):  
Intracellular Signaling ◽  
Critical Role ◽  
Membrane Traffic ◽  
New Information ◽  
Selective Incorporation ◽  
Lipid Kinases ◽  
Membrane Compartments ◽  
Epidermal Growth ◽  
And Function

Phosphoinositides (PIPs) are important regulators of various cellular phenomena including intracellular signaling, membrane traffic and cell migration. PIPs are formed as a result of the regulated phosphorylation of the inositol headgroup of phosphatidylinositol (PI) on specific positions by certain lipid kinases and phosphatases. It is well appreciated that the enrichment of specific PIPs, defined by inositol headgroup phosphorylation, within specific membrane compartments plays a critical role in organelle identity and membrane traffic. However, while much attention has been given to understanding of the role of inositol headgroup phosphorylation in PIP function, much less is known about the role of dynamic incorporation of specific acyl groups into these phospholipids. Importantly, PI and PIPs exhibit remarkable and unique selectivity for certain acyl groups. For example, about 45% of PIs (but not other phospholipids) are rich in 1-steroyl 2-arachidonyl. We recently identified that the possible control of the selective incorporation of steric acid at the sn-1 position is by the acyltransferase LYCAT, which controls the levels, acyl profile and function of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) (Bone et al. Mol Biol Cell 2017. 28:161-172). Here we examine how perturbation of LYCAT leads to a reduction in the levels of PI(4,5)P2 and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3). To measure the rate of PI(4,5)P2 synthesis, we treated cells with ionomycin to first ablate this PIP, followed by washout of the drug and monitoring of rate of reappearance via localization of a fluorescent PI(4,5)P2 probe. To measure the rate of PI(4,5)P2 degradation, we arrested PI(4,5)P2 synthesis by a pharmacological inhibitor, phenylarsine oxide (PAO) and monitored the loss of cellular PI(4,5)P2. Lastly, to examine the production of PI(3,4,5)P3, we treated cells with epidermal growth factor (EGF) and monitored the production of this PIP. Together, this work provides new information about how the dynamic and selective remodeling of specific phospholipids controls their levels, localization and function.

scholarly journals Control Of Phosphoinositide Synthesis And Degradation By The Acyltransferase Lycat

2021 ◽  
Author(s):  
Yasmin Awadeh
Keyword(s):  
Intracellular Signaling ◽  
Critical Role ◽  
Membrane Traffic ◽  
New Information ◽  
Selective Incorporation ◽  
Lipid Kinases ◽  
Membrane Compartments ◽  
Epidermal Growth ◽  
And Function

Phosphoinositides (PIPs) are important regulators of various cellular phenomena including intracellular signaling, membrane traffic and cell migration. PIPs are formed as a result of the regulated phosphorylation of the inositol headgroup of phosphatidylinositol (PI) on specific positions by certain lipid kinases and phosphatases. It is well appreciated that the enrichment of specific PIPs, defined by inositol headgroup phosphorylation, within specific membrane compartments plays a critical role in organelle identity and membrane traffic. However, while much attention has been given to understanding of the role of inositol headgroup phosphorylation in PIP function, much less is known about the role of dynamic incorporation of specific acyl groups into these phospholipids. Importantly, PI and PIPs exhibit remarkable and unique selectivity for certain acyl groups. For example, about 45% of PIs (but not other phospholipids) are rich in 1-steroyl 2-arachidonyl. We recently identified that the possible control of the selective incorporation of steric acid at the sn-1 position is by the acyltransferase LYCAT, which controls the levels, acyl profile and function of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) (Bone et al. Mol Biol Cell 2017. 28:161-172). Here we examine how perturbation of LYCAT leads to a reduction in the levels of PI(4,5)P2 and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3). To measure the rate of PI(4,5)P2 synthesis, we treated cells with ionomycin to first ablate this PIP, followed by washout of the drug and monitoring of rate of reappearance via localization of a fluorescent PI(4,5)P2 probe. To measure the rate of PI(4,5)P2 degradation, we arrested PI(4,5)P2 synthesis by a pharmacological inhibitor, phenylarsine oxide (PAO) and monitored the loss of cellular PI(4,5)P2. Lastly, to examine the production of PI(3,4,5)P3, we treated cells with epidermal growth factor (EGF) and monitored the production of this PIP. Together, this work provides new information about how the dynamic and selective remodeling of specific phospholipids controls their levels, localization and function.

scholarly journals The acyltransferase LYCAT controls specific phosphoinositides and related membrane traffic

2017 ◽  
Vol 28 (1) ◽  
pp. 161-172 ◽  
Author(s):  
Leslie N. Bone ◽  
Roya M. Dayam ◽  
Minhyoung Lee ◽  
Nozomu Kono ◽  
Gregory D. Fairn ◽  
...  
Keyword(s):  
Acyl Chain ◽  
Membrane Traffic ◽  
Cell Physiology ◽  
Phosphatidylinositol Synthase ◽  
Lipid Kinases ◽  
Acyl Chains ◽  
And Function ◽  
Phosphatidylinositol 4 ◽  
Phosphatidylinositol 3

Phosphoinositides (PIPs) are key regulators of membrane traffic and signaling. The interconversion of PIPs by lipid kinases and phosphatases regulates their functionality. Phosphatidylinositol (PI) and PIPs have a unique enrichment of 1-stearoyl-2-arachidonyl acyl species; however, the regulation and function of this specific acyl profile remains poorly understood. We examined the role of the PI acyltransferase LYCAT in control of PIPs and PIP-dependent membrane traffic. LYCAT silencing selectively perturbed the levels and localization of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] and phosphatidylinositol-3-phosphate and the membrane traffic dependent on these specific PIPs but was without effect on phosphatidylinositol-4-phosphate or biosynthetic membrane traffic. The acyl profile of PI(4,5)P2 was selectively altered in LYCAT-deficient cells, whereas LYCAT localized with phosphatidylinositol synthase. We propose that LYCAT remodels the acyl chains of PI, which is then channeled into PI(4,5)P2. Our observations suggest that the PIP acyl chain profile may exert broad control of cell physiology.

scholarly journals Disruption of cytoskeletal integrity impairs Gi-mediated signaling due to displacement of Gi proteins

2001 ◽  
Vol 154 (4) ◽  
pp. 753-762 ◽  
Author(s):  
Wilhelm Bloch ◽  
Yun Fan ◽  
Ji Han ◽  
Sheng Xue ◽  
Torsten Schöneberg ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Critical Role ◽  
Embryonic Stem ◽  
Β1 Integrin ◽  
G Protein Coupling ◽  
Intracellular Signaling Pathways ◽  
Β1 Integrins ◽  
K Current ◽  
And Function

β1 integrins play a crucial role as cytoskeletal anchorage proteins. In this study, the coupling of the cytoskeleton and intracellular signaling pathways was investigated in β1 integrin deficient (−/−) embryonic stem cells. Muscarinic inhibition of the L-type Ca2+ current (ICa) and activation of the acetylcholine-activated K+ current (IK,ACh) was found to be absent in β1 integrin−/− cardiomyocytes. Conversely, β adrenoceptor-mediated modulation of ICa was unaffected by the absence of β1 integrins. This defect in muscarinic signaling was due to defective G protein coupling. This was supported by deconvolution microscopy, which demonstrated that Gi exhibited an atypical subcellular distribution in the β1 integrin−/− cardiomyocytes. A critical role of the cytoskeleton was further demonstrated using cytochalasin D, which displaced Gi and impaired muscarinic signaling. We conclude that cytoskeletal integrity is required for correct localization and function of Gi-associated signaling microdomains.

Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

scholarly journals The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review

2021 ◽  
Vol 22 (9) ◽  
pp. 4370
Author(s):  
Cássia de Fáveri ◽  
Paula M. Poeta Fermino ◽  
Anna P. Piovezan ◽  
Lia K. Volpato
Keyword(s):  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Integrative Review ◽  
Inflammatory Factors ◽  
Resolvin D1 ◽  
Endogenous Factors

The pathogenesis of endometriosis is still controversial, although it is known that the inflammatory immune response plays a critical role in this process. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis. The mechanisms by which pro-resolving mediators (PRM) act in endometriosis are still little explored. Thus, this integrative review aims to synthesize the available content regarding the role of PRM in endometriosis. Experimental and in vitro studies with Lipoxin A4 demonstrate a potential inhibitory effect on endometrial lesions’ progression, attenuating pro-inflammatory and angiogenic signals, inhibiting proliferative and invasive action suppressing intracellular signaling induced by cytokines and estradiol, mainly through the FPR2/ALX. Investigations with Resolvin D1 demonstrated the inhibition of endometrial lesions and decreased pro-inflammatory factors. Annexin A1 is expressed in the endometrium and is specifically present in women with endometriosis, although the available studies are still inconsistent. Thus, we believe there is a gap in knowledge regarding the PRM pathways in patients with endometriosis. It is important to note that these substances’ therapeutic potential is evident since the immune and abnormal inflammatory responses play an essential role in endometriosis development and progression.

The Pleiotropic Intricacies of Hedgehog Signaling: From Craniofacial Patterning to Carcinogenesis

FACE ◽  
2021 ◽  
pp. 273250162110243
Author(s):  
Mikhail Pakvasa ◽  
Andrew B. Tucker ◽  
Timothy Shen ◽  
Tong-Chuan He ◽  
Russell R. Reid
Keyword(s):  
Intracellular Signaling ◽  
Limb Development ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Craniofacial Development ◽  
Signaling Cascade ◽  
Signaling Mechanisms ◽  
Intracellular Signaling Cascade ◽  
And Function

Hedgehog signaling was discovered more than 40 years ago in experiments demonstrating that it is a fundamental mediator of limb development. Since that time, it has been shown to be important in development, homeostasis, and disease. The hedgehog pathway proceeds through a pathway highly conserved throughout animals beginning with the extracellular diffusion of hedgehog ligands, proceeding through an intracellular signaling cascade, and ending with the activation of specific target genes. A vast amount of research has been done elucidating hedgehog signaling mechanisms and regulation. This research has found a complex system of genetics and signaling that helps determine how organisms develop and function. This review provides an overview of what is known about hedgehog genetics and signaling, followed by an in-depth discussion of the role of hedgehog signaling in craniofacial development and carcinogenesis.

A Review on Role of Macro and Micro Banking Environment on Non-Performing Assets Management

2019 ◽  
pp. 281-294
Author(s):  
Biswajit Prasad Chhatoi ◽  
Sharada Prasad Sahoo
Keyword(s):  
Critical Role ◽  
Banking System ◽  
Financial Assets ◽  
Policy Changes ◽  
Public And Private ◽  
Private Banks ◽  
Specific Factors ◽  
And Function ◽  
Asset Creation

In a self-resilient economy, banking system assumes importance in imparting momentum to economic growth and prosperity through mobilization of financial assets. Performance of banks, irrespective of their nature and function, is germane to their asset creation and maintenance capacity. In a neo-liberal regime, radical policy changes have crept into loan mechanism, thereby subjecting the banks to efficiently recover the loans, which is a vital asset for any banking firm. In this context, the authors through intensive review of literature identified micro and macro banking factors responsible for productive NPA management. The macro banking factors refer to the economic environment whereas the micro banking factors refer to the bank and branch-specific factors. The authors identified the critical role of organizational structure, involvement of employees, and organizational efficiency in driving prudent NPA management. The authors have found that the efficiency in managing NPAs differ in public and private banks, which is attributed to involvement of employees.

scholarly journals Calcium Regulates HCC Proliferation as well as EGFR Recycling/Degradation and Could Be a New Therapeutic Target in HCC

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1588 ◽  
Author(s):  
Teresa Maria Elisa Modica ◽  
Francesco Dituri ◽  
Serena Mancarella ◽  
Claudio Pisano ◽  
Isabel Fabregat ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Therapeutic Target ◽  
Intracellular Signaling ◽  
Growth Factor Receptor ◽  
The Body ◽  
Biochemical Processes ◽  
Epidermal Growth ◽  
Abundant Element

Calcium is the most abundant element in the human body. Its role is essential in physiological and biochemical processes such as signal transduction from outside to inside the cell between the cells of an organ, as well as the release of neurotransmitters from neurons, muscle contraction, fertilization, bone building, and blood clotting. As a result, intra- and extracellular calcium levels are tightly regulated by the body. The liver is the most specialized organ of the body, as its functions, carried out by hepatocytes, are strongly governed by calcium ions. In this work, we analyze the role of calcium in human hepatoma (HCC) cell lines harboring a wild type form of the Epidermal Growth Factor Receptor (EGFR), particularly its role in proliferation and in EGFR downmodulation. Our results highlight that calcium is involved in the proliferative capability of HCC cells, as its subtraction is responsible for EGFR degradation by proteasome machinery and, as a consequence, for EGFR intracellular signaling downregulation. However, calcium-regulated EGFR signaling is cell line-dependent. In cells responding weakly to the epidermal growth factor (EGF), calcium seems to have an opposite effect on EGFR internalization/degradation mechanisms. These results suggest that besides EGFR, calcium could be a new therapeutic target in HCC.

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