scholarly journals Identification of a new regulation pathway of EGFR and E-cadherin dynamics

2020 ◽  
Author(s):  
Veronique Proux-Gillardeaux ◽  
Tamara Advedissian ◽  
Charlotte Perin ◽  
Jean-Christophe Gelly ◽  
Mireille Viguier ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Direct Interaction ◽  
Endocytic Pathway ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Epithelial Homeostasis ◽  
Proliferation And Differentiation ◽  
E Cadherin

ABSTRACTEGFR plays key roles in multiple cellular processes such as cell differentiation, cell proliferation, migration and epithelia homeostasis. Phosphorylation of the receptor, intracellular signaling and trafficking are major events regulating EGFR functions. Galectin-7, a soluble lectin expressed in epithelia such as the skin, has been shown to be involved in cell differentiation. Through this study we demonstrate that galectin-7 regulates EGFR function by a direct interaction with its extracellular domain hence modifying its downstream signaling and endocytic pathway. From observations in mice we focused on the molecular mechanisms deciphering the glycosylation dependent interaction between EGFR and galectin-7. Interestingly, we also revealed that galectin-7 is a direct binder of both EGFR and E-cadherin bridging them together. Strikingly this study not only deciphers a new molecular mechanism of EGFR regulation but also points out a novel molecular interaction between EGFR and E-cadherin, two major regulators of the balance between proliferation and differentiation.SUMMARYEGFR and E-cadherin are known to interact and to regulate epithelial homeostasis. In this study we unravel in the epidermis a new partner and regulator of EGFR which also binds E-cadherin reciprocally bridging their dynamics and functions.

Abstract 497: Cholesterol and Toll-like Receptor Signaling Are Important Regulators of Macrophage Interactions with Atherosclerotic Lipoprotein Aggregates

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Harvey F Chin ◽  
Abigail Haka ◽  
Frederick R Maxfield
Keyword(s):  
Molecular Mechanisms ◽  
Atherosclerotic Plaques ◽  
Cholesteryl Esters ◽  
Cellular Mechanisms ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Atherosclerotic Plaque Formation ◽  
Subendothelial Space ◽  
Morphological Responses ◽  
Cytoskeletal Rearrangements

Macrophages encounter deposits of aggregated low-density lipoproteins (agLDL) in the subendothelial space of blood vessels during the first stages of atherosclerotic plaque formation. Notably, current models for the mechanism of macrophage internalization of cholesterol in early atherosclerotic plaques are incomplete due to the lack of attention paid to the unique cellular mechanisms that are required for macrophages to degrade aggregates of LDL in particular, which can comprise >90% of the LDL in atherosclerotic plaques. In fact, internalization of cholesterol from cholesteryl esters in agLDL involves the development of intriguing cellular processes in which extracellular acidic compartments, lysosomal synapses (LSs), are formed whereby agLDL is partially degraded prior to internalization. This process requires extensive cytoskeletal rearrangements and secretion of lysosomal enzymes responsible for hydrolysis of cholesteryl esters from the agLDL. Subsequent delivery of free cholesterol from agLDL to the macrophage plasma membrane is central for development of the LS. Nonetheless, the molecular mechanism underlying initiation and propagation of the LS are currently largely unknown. This research proposal aims to elucidate the molecular mechanisms of LS formation and the role that cholesterol plays in eliciting these morphological responses to agLDL. Fluorescence microscopy assays were used to identify activation of TLR4 and downstream signaling involving PI3K and Akt as important events leading to LS formation. Furthermore, morphological responses of macrophages to cholesterol overloading require overlapping signaling pathways, indicating the role of interplay of cholesterol and TLR4 signaling in development of this novel macrophage interaction with aggregated LDL found in plaques. Identification of specific molecular pathways involved in this process will not only contribute to the basic understanding of one of the primary cellular processes contributing to atherosclerosis, one of the primary causes of heart disease, but also provide tangible molecular targets for the ultimate development of therapies.

scholarly journals IQGAP1 binds AMPK and is required for maximum AMPK activation

2020 ◽  
pp. jbc.RA120.016193
Author(s):  
Andrew C. Hedman ◽  
Zhigang Li ◽  
Laëtitia Gorisse ◽  
Swetha Parvathaneni ◽  
Chase J. Morgan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Direct Interaction ◽  
Mitogen Activated Protein Kinase ◽  
Null Cell ◽  
Ampk Signaling ◽  
In Cells

AMP-activated protein kinase (AMPK) is a fundamental component of a protein kinase cascade that is an energy sensor. AMPK maintains energy homeostasis in the cell by promoting catabolic and inhibiting anabolic pathways. Activation of AMPK requires phosphorylation by the liver kinase B1 or by the Ca2+ /calmodulin-dependent protein kinase kinase 2 (CaMKK2). The scaffold protein IQGAP1 regulates intracellular signaling pathways, such as the mitogen-activated protein kinase and AKT signaling cascades. Recent work implicates the participation of IQGAP1 in metabolic function, but the molecular mechanisms underlying these effects are poorly understood. Here, using several approaches including binding analysis with fusion proteins, siRNA-mediated gene silencing, RT-PCR, and knockout mice, we investigated whether IQGAP1 modulates AMPK signaling. In vitro analysis reveals that IQGAP1 binds directly to the α1 subunit of AMPK. In addition, we observed a direct interaction between IQGAP1 and CaMKK2, which is mediated by the IQ domain of IQGAP1. Both CaMKK2 and AMPK associate with IQGAP1 in cells. The ability of metformin and increased intracellular free Ca2+ concentrations to activate AMPK is reduced in cells lacking IQGAP1. Importantly, Ca2+-stimulated AMPK phosphorylation was rescued by re-expression of IQGAP1 in IQGAP1-null cell lines. Comparison of the fasting response in wild-type and IQGAP1-null mice revealed that transcriptional regulation of the gluconeogenesis genes PCK1 and G6PC and the fatty acid synthesis genes FASN and ACC1 is impaired in IQGAP1-null mice. Our data disclose a previously unidentified functional interaction between IQGAP1 and AMPK and suggest that IQGAP1 modulates AMPK signaling.

Molecular mechanisms of action and physiological effects of the proinsulin C-peptide (a systematic review)

2020 ◽  
Vol 66 (3) ◽  
pp. 196-207
Author(s):  
O.N. Poteryaeva ◽  
I.F. Usynin
Keyword(s):  
Intracellular Signaling ◽  
Defense Mechanisms ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Physiological Effects ◽  
C Peptide ◽  
Downstream Signaling ◽  
Blood Microcirculation ◽  
Patients With Diabetes

The C-peptide is a fragment of proinsulin, the cleavage of which forms active insulin. In recent years, new information has appeared on the physiological effects of the C-peptide, indicating its positive effect on many organs and tissues, including the kidneys, nervous system, heart, vascular endothelium and blood microcirculation. Studies on experimental models of diabetes mellitus in animals, as well as clinical trials in patients with diabetes, have shown that the C-peptide has an important regulatory effect on the early stages of functional and structural disorders caused by this disease. The C-peptide exhibits its effects through binding to a specific receptor on the cell membrane and activation of downstream signaling pathways. Intracellular signaling involves G-proteins and Ca2+-dependent pathways, resulting in activation and increased expression of endothelial nitric oxide synthase, Na+/K+-ATPase and important transcription factors involved in apoptosis, anti-inflammatory and other intracellular defense mechanisms. This review gives an idea of the C-peptide as a bioactive endogenous peptide that has its own biological activity and therapeutic potential.

Immunocytochemical Detection of Phosphatidylinositol 3-kinase Activation by Insulin and Leptin

2003 ◽  
Vol 51 (3) ◽  
pp. 275-283 ◽  
Author(s):  
Kevin D. Niswender ◽  
Byron Gallis ◽  
James E. Blevins ◽  
Marshall A. Corson ◽  
Michael W. Schwartz ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Serine Phosphorylation ◽  
Phosphatidylinositol 3 Kinase ◽  
Aortic Endothelial Cells ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Pi3k Activity ◽  
Pi3k Activation ◽  
Hepatic Portal ◽  
Phosphatidylinositol 3

Intracellular signaling mediated by phosphatidylinositol 3-kinase (PI3K) is important for a number of cellular processes and is stimulated by a variety of hormones, including insulin and leptin. A histochemical method for assessment of PI3K signaling would be an important advance in identifying specific cells in histologically complex organs that are regulated by growth factors and peptide hormones. However, current methods for detecting PI3K activity require either homogenization of the tissue or cells or the ability to transfect probes that bind to phosphatidylinositol 3,4,5 trisphosphate (PIP3), the reaction product of PI3K catalysis. Here we report the validation of an immunocytochemical method to detect changes in PI3K activity, using a recently developed monoclonal antibody to PIP3, in paraformaldehyde-fixed bovine aortic endothelial cells (BAECs) in culture and in hepatocytes of intact rat liver. Treatment with either insulin or leptin increased BAEC PIP3 immunoreactivity, and these effects were blocked by pretreatment with PI3K inhibitors. Furthermore, infusion of insulin into the hepatic portal vein of fasted rats caused an increase of PIP3 immunostaining in hepatocytes that was associated with increased serine phosphorylation of the downstream signaling molecule protein kinase B/Akt (PKB/Akt). We conclude that immunocytochemical PIP3 staining can detect changes in PI3K activation induced by insulin and leptin in cell culture and intact liver.

scholarly journals Novel Toolboxes for the Investigation of Activity-Dependent Myelination in the Central Nervous System

2021 ◽  
Vol 15 ◽  
Author(s):  
Jack Kent Heflin ◽  
Wenjing Sun
Keyword(s):  
Cell Interaction ◽  
Precursor Cells ◽  
Signaling Cascades ◽  
Initial Contact ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Proliferation And Differentiation ◽  
The Central Nervous System ◽  
Underlying Mechanisms ◽  
Activity Dependent

Myelination is essential for signal processing within neural networks. Emerging data suggest that neuronal activity positively instructs myelin development and myelin adaptation during adulthood. However, the underlying mechanisms controlling activity-dependent myelination have not been fully elucidated. Myelination is a multi-step process that involves the proliferation and differentiation of oligodendrocyte precursor cells followed by the initial contact and ensheathment of axons by mature oligodendrocytes. Conventional end-point studies rarely capture the dynamic interaction between neurons and oligodendrocyte lineage cells spanning such a long temporal window. Given that such interactions and downstream signaling cascades are likely to occur within fine cellular processes of oligodendrocytes and their precursor cells, overcoming spatial resolution limitations represents another technical hurdle in the field. In this mini-review, we discuss how advanced genetic, cutting-edge imaging, and electrophysiological approaches enable us to investigate neuron-oligodendrocyte lineage cell interaction and myelination with both temporal and spatial precision.

scholarly journals The hypoxic expression of the glucose transporter RAG1 reveals the role of the bHLH transcription factor Sck1 as a novel hypoxic modulator in Kluyveromyces lactis

2019 ◽  
Vol 19 (4) ◽  
Author(s):  
Rosa Santomartino ◽  
Daniela Ottaviano ◽  
Ilaria Camponeschi ◽  
Tracy Ann Alcarpio Landicho ◽  
Luca Falato ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Kluyveromyces Lactis ◽  
Transcriptional Activator ◽  
Bhlh Transcription Factor ◽  
Cellular Processes ◽  
Hypoxic Induction ◽  
Rag1 Gene

ABSTRACTGlucose is the preferred nutrient for most living cells and is also a signaling molecule that modulates several cellular processes. Glucose regulates the expression of glucose permease genes in yeasts through signaling pathways dependent on plasma membrane glucose sensors. In the yeast Kluyveromyces lactis, sufficient levels of glucose induction of the low-affinity glucose transporter RAG1 gene also depends on a functional glycolysis, suggesting additional intracellular signaling. We have found that the expression of RAG1 gene is also induced by hypoxia in the presence of glucose, indicating that glucose and oxygen signaling pathways are interconnected. In this study we investigated the molecular mechanisms underlying this crosstalk. By analyzing RAG1 expression in various K. lactis mutants, we found that the bHLH transcriptional activator Sck1 is required for the hypoxic induction of RAG1 gene. The RAG1 promoter region essential for its hypoxic induction was identified by promoter deletion experiments. Taken together, these results show that the RAG1 glucose permease gene is synergistically induced by hypoxia and glucose and highlighted a novel role for the transcriptional activator Sck1 as a key mediator in this mechanism.

Effect of Octacalcium Phosphate Ionic Dissolution Products on Osteoblastic Cell Differentiation

2007 ◽  
Vol 361-363 ◽  
pp. 31-34 ◽  
Author(s):  
Takahisa Anada ◽  
Akihiro Araseki ◽  
Shou Matsukawa ◽  
Tomokazu Yamasaki ◽  
Shinji Kamakura ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Conditioned Medium ◽  
Molecular Mechanisms ◽  
Octacalcium Phosphate ◽  
Osteoblastic Cell ◽  
Mouse Bone Marrow ◽  
Phosphate Ions ◽  
Proliferation And Differentiation

Our previous studies suggested that synthetic octacalcium phosphate (OCP) enhances bone regeneration more than hydroxyapatite (HA). However, the molecular mechanisms to induce osteogenic phenotype in osteoblast by OCP have not been identified. OCP tended to convert into an apatite structure in vivo and in vitro, and its process was accompanied by calcium consumption from the surrounding solution and the release of phosphate ions into the solution at a physiological condition. The present study was designed to investigate whether the dissolution of ionic products of OCP affects on proliferation and differentiation of mouse bone marrow stromal ST-2 cells in vitro. The number of cells treated with OCP-conditioned medium was slightly decreased in comparison to that of control at day 7. On the other hand, the level of alkaline phosphatase activity increased in OCP-conditioned medium. These results demonstrated that OCP is capable of inducing osteoblastic cell differentiation in ST-2 cells.

scholarly journals Human CLASP2 specifically regulates microtubule catastrophe and rescue

2018 ◽  
Vol 29 (10) ◽  
pp. 1168-1177 ◽  
Author(s):  
Elizabeth J. Lawrence ◽  
Göker Arpag˘ ◽  
Stephen R. Norris ◽  
Marija Zanic
Keyword(s):  
Growth Rates ◽  
Molecular Mechanisms ◽  
Direct Interaction ◽  
Microtubule Dynamics ◽  
Microtubule Associated Proteins ◽  
Cellular Processes ◽  
Associated Proteins ◽  
Microtubule Growth ◽  
Protein Components

Cytoplasmic linker-associated proteins (CLASPs) are microtubule-associated proteins essential for microtubule regulation in many cellular processes. However, the molecular mechanisms underlying CLASP activity are not understood. Here, we use purified protein components and total internal reflection fluorescence microscopy to investigate the effects of human CLASP2 on microtubule dynamics in vitro. We demonstrate that CLASP2 suppresses microtubule catastrophe and promotes rescue without affecting the rates of microtubule growth or shrinkage. Strikingly, when CLASP2 is combined with EB1, a known binding partner, the effects on microtubule dynamics are strongly enhanced. We show that synergy between CLASP2 and EB1 is dependent on a direct interaction, since a truncated EB1 protein that lacks the CLASP2-binding domain does not enhance CLASP2 activity. Further, we find that EB1 targets CLASP2 to microtubules and increases the dwell time of CLASP2 at microtubule tips. Although the temporally averaged microtubule growth rates are unaffected by CLASP2, we find that microtubules grown with CLASP2 display greater variability in growth rates. Our results provide insight into the regulation of microtubule dynamics by CLASP proteins and highlight the importance of the functional interplay between regulatory proteins at dynamic microtubule ends.

scholarly journals Integrin Signaling in Oligodendrocytes and Its Importance in CNS Myelination

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Ryan W. O'Meara ◽  
John-Paul Michalski ◽  
Rashmi Kothary
Keyword(s):  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Disease Process ◽  
Cell Phenotype ◽  
Developmentally Regulated ◽  
Transmembrane Receptors ◽  
Downstream Signaling ◽  
Signaling Axis ◽  
The Central Nervous System ◽  
Cns Myelination

Multiple sclerosis is characterized by repeated demyelinating attacks of the central nervous system (CNS) white matter tracts. To tailor novel therapeutics to halt or reverse disease process, we require a better understanding of oligodendrocyte biology and of the molecular mechanisms that initiate myelination. Cell extrinsic mechanisms regulate CNS myelination through the interaction of extracellular matrix proteins and their transmembrane receptors. The engagement of one such receptor family, the integrins, initiates intracellular signaling cascades that lead to changes in cell phenotype. Oligodendrocytes express a diverse array of integrins, and the expression of these receptors is developmentally regulated. Integrin-mediated signaling is crucial to the proliferation, survival, and maturation of oligodendrocytes through the activation of downstream signaling pathways involved in cytoskeletal remodeling. Here, we review the current understanding of this important signaling axis and its role in oligodendrocyte biology and ultimately in the myelination of axons within the CNS.

scholarly journals Notch Signaling Regulation in Autoinflammatory Diseases

2020 ◽  
Vol 21 (22) ◽  
pp. 8847
Author(s):  
Rossella Gratton ◽  
Paola Maura Tricarico ◽  
Adamo Pio d'Adamo ◽  
Anna Monica Bianco ◽  
Ronald Moura ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Notch Pathway ◽  
Autoinflammatory Diseases ◽  
Cellular Processes ◽  
Core Components

Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.

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