scholarly journals Coordinating ERK signaling via the molecular scaffold Kinase Suppressor of Ras

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1621 ◽  
Author(s):  
Danielle Frodyma ◽  
Beth Neilsen ◽  
Diane Costanzo-Garvey ◽  
Kurt Fisher ◽  
Robert Lewis
Keyword(s):  
Energy Balance ◽  
Small Molecule ◽  
Physiological Role ◽  
Molecular Scaffolds ◽  
Potent Effect ◽  
Molecular Scaffold ◽  
Kinase Suppressor Of Ras ◽  
Kinase Cascade ◽  
Reduced Toxicity ◽  
Erk Kinase

Many cancers, including those of the colon, lung, and pancreas, depend upon the signaling pathways induced by mutated and constitutively active Ras. The molecular scaffolds Kinase Suppressor of Ras 1 and 2 (KSR1 and KSR2) play potent roles in promoting Ras-mediated signaling through the Raf/MEK/ERK kinase cascade. Here we summarize the canonical role of KSR in cells, including its central role as a scaffold protein for the Raf/MEK/ERK kinase cascade, its regulation of various cellular pathways mediated through different binding partners, and the phenotypic consequences of KSR1 or KSR2 genetic inactivation. Mammalian KSR proteins have a demonstrated role in cellular and organismal energy balance with implications for cancer and obesity. Targeting KSR1 in cancer using small molecule inhibitors has potential for therapy with reduced toxicity to the patient. RNAi and small molecule screens using KSR1 as a reference standard have the potential to expose and target vulnerabilities in cancer. Interestingly, although KSR1 and KSR2 are similar in structure, KSR2 has a distinct physiological role in regulating energy balance. Although KSR proteins have been studied for two decades, additional analysis is required to elucidate both the regulation of these molecular scaffolds and their potent effect on the spatial and temporal control of ERK activation in health and disease.

scholarly journals The Molecular Scaffold Kinase Suppressor of Ras 1 (KSR1) Regulates Adipogenesis

2005 ◽  
Vol 25 (17) ◽  
pp. 7592-7604 ◽  
Author(s):  
Robert L. Kortum ◽  
Diane L. Costanzo ◽  
Jamie Haferbier ◽  
Steven J. Schreiner ◽  
Gina L. Razidlo ◽  
...  
Keyword(s):  
Cell Fate ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Molecular Scaffold ◽  
Kinase Suppressor Of Ras ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Ribosomal S6 Kinase

ABSTRACT Mitogen-activated protein kinase pathways are implicated in the regulation of cell differentiation, although their precise roles in many differentiation programs remain elusive. The Raf/MEK/extracellular signal-regulated kinase (ERK) kinase cascade has been proposed to both promote and inhibit adipogenesis. Here, we titrate expression of the molecular scaffold kinase suppressor of Ras 1 (KSR1) to regulate signaling through the Raf/MEK/ERK/p90 ribosomal S6 kinase (RSK) kinase cascade and show how it determines adipogenic potential. Deletion of KSR1 prevents adipogenesis in vitro, which can be rescued by introduction of low levels of KSR1. Appropriate levels of KSR1 coordinate ERK and RSK activation with C/EBPβ synthesis leading to the phosphorylation and stabilization of C/EBPβ at the precise moment it is required within the adipogenic program. Elevated levels of KSR1 expression, previously shown to enhance cell proliferation, promote high, sustained ERK activation that phosphorylates and inhibits peroxisome proliferator-activated receptor gamma, inhibiting adipogenesis. Titration of KSR1 expression reveals how a molecular scaffold can modulate the intensity and duration of signaling emanating from a single pathway to dictate cell fate.

Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness

2021 ◽  
Author(s):  
Jiongjia Cheng ◽  
Masanao Tsuda ◽  
Karl Okolotowicz ◽  
Mary Dwyer ◽  
Paul J. Bushway ◽  
...  
Keyword(s):  
Small Molecule ◽  
Stress Signaling ◽  
Kinase Cascade ◽  
Small Molecule Probe

scholarly journals Identification of Ste4 as a potential regulator of Byr2 in the sexual response pathway of Schizosaccharomyces pombe.

1996 ◽  
Vol 16 (10) ◽  
pp. 5597-5603 ◽  
Author(s):  
M M Barr ◽  
H Tu ◽  
L Van Aelst ◽  
M Wigler
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Schizosaccharomyces Pombe ◽  
Binding Site ◽  
Sexual Differentiation ◽  
Leucine Zipper ◽  
Regulatory Region ◽  
Map Kinase Cascade ◽  
Kinase Cascade ◽  
Two Hybrid ◽  
Erk Kinase

A conserved MAP kinase cascade is central to signal transduction in both simple and complex eukaryotes. In the yeast Schizosaccharomyces pombe, Byr2, a homolog of mammalian MAPK/ERK kinase kinase and Saccharomyces cerevisiae STE11, is required for pheromone-induced sexual differentiation. A screen for S. pombe proteins that interact with Byr2 in a two-hybrid system led to the isolation of Ste4, a protein that is known to be required for sexual function. Ste4 binds to the regulatory region of Byr2. This binding site is separable from the binding site for Ras1. Both Ste4 and Ras1 act upstream of Byr2 and act at least partially independently. Ste4 contains a leucine zipper and is capable of homotypic interaction. Ste4 has regions of homology with STE50, an S. cerevisiae protein required for sexual differentiation that we show can bind to STE11.

scholarly journals Recent Advances in Flavin-Dependent Halogenase Biocatalysis: Sourcing, Engineering, and Application

Catalysts ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 1030 ◽  
Author(s):  
Johannes Büchler ◽  
Athena Papadopoulou ◽  
Rebecca Buller
Keyword(s):  
Small Molecule ◽  
Halogen Atom ◽  
Reaction Engineering ◽  
Special Focus ◽  
Molecular Scaffolds ◽  
Reaction Conditions ◽  
Bioactive Substances ◽  
Application Range ◽  
Technological Value ◽  
Recent Developments

The introduction of a halogen atom into a small molecule can effectively modulate its properties, yielding bioactive substances of agrochemical and pharmaceutical interest. Consequently, the development of selective halogenation strategies is of high technological value. Besides chemical methodologies, enzymatic halogenations have received increased interest as they allow the selective installation of halogen atoms in molecular scaffolds of varying complexity under mild reaction conditions. Today, a comprehensive library of aromatic halogenases exists, and enzyme as well as reaction engineering approaches are being explored to broaden this enzyme family’s biocatalytic application range. In this review, we highlight recent developments in the sourcing, engineering, and application of flavin-dependent halogenases with a special focus on chemoenzymatic and coupled biosynthetic approaches.

scholarly journals Update in TSH Receptor Agonists and Antagonists

2012 ◽  
Vol 97 (12) ◽  
pp. 4287-4292 ◽  
Author(s):  
Marvin C. Gershengorn ◽  
Susanne Neumann
Keyword(s):  
Thyroid Function ◽  
Small Molecule ◽  
Physiological Role ◽  
Tsh Receptor ◽  
Thyroid Tumors ◽  
Inverse Agonists ◽  
Small Molecule Drug ◽  
Pathological Conditions ◽  
Receptor Agonists And Antagonists

The physiological role of the TSH receptor (TSHR) as a major regulator of thyroid function is well understood, but TSHRs are also expressed in multiple normal extrathyroidal tissues, and the physiological roles of TSHRs in these tissues are unclear. Moreover, TSHRs play a major role in several pathological conditions including hyperthyroidism, hypothyroidism, and thyroid tumors. Small molecule, “drug-like” TSHR agonists, neutral antagonists, and inverse agonists may be useful as probes of TSHR function in extrathyroidal tissues and as leads to develop drugs for several diseases of the thyroid. In this Update, we review the most recent findings regarding the development and use of these small molecule TSHR ligands.

Small-Molecule Screen Identifies ROS as Key Regulators of Actin Dynamics in Neutrophils

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4641-4641
Author(s):  
Hidenori Hattori ◽  
Kulandayan K Subramanian ◽  
Hongbo R. Luo
Keyword(s):  
Small Molecule ◽  
Actin Polymerization ◽  
Neutrophil Migration ◽  
Physiological Role ◽  
Leading Edge ◽  
Actin Dynamics ◽  
Functional Screening ◽  
Cellular Processes

Abstract Precise spatial and temporal control of actin polymerization and depolymerization is essential for mediating various cellular processes such as migration, phagocytosis, vesicle trafficking and adhesion. In this study, we used a small-molecule functional screening approach to identify novel regulators of actin dynamics during neutrophil migration. Here we show that NADPH-oxidase dependent Reactive Oxygen Species act as negative regulators of actin polymerization. Neutrophils with pharmacologically inhibited oxidase or isolated from Chronic Granulomatous Disease (CGD) patient and mice displayed enhanced F-actin polymerization, multiple pseudopods formation and impaired chemotaxis. ROS localized to pseudopodia and inhibited actin polymerization by driving actin glutathionylation at the leading edge of migrating cells. Consistent with these in vitro results, adoptively transferred CGD murine neutrophils also showed impaired in vivo recruitment to sites of inflammation. Together, these results present a novel physiological role for ROS in regulation of action polymerization and shed new light on the pathogenesis of CGD.

Genomics and proteomics-based discovery of novel cancer biomarkers and molecular targets for cell-permeable peptide/small molecule-based drugs.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13552-e13552
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Tissue Microarray ◽  
Small Molecule ◽  
Phosphorylation Site ◽  
Lung Cancer Cells ◽  
Lung Cancers ◽  
Genomics And Proteomics ◽  
Cell Permeable Peptide ◽  
Erk Kinase

e13552 Background: Identification of cancer-specific oncoproteins is an effective approach to develop new diagnostics and therapeutics. Methods: We have established a strategy as follows to identify new oncoproteins, which can be applied as biomarkers and drug development; i) To identify genes overexpressed in 120 clinical lung cancers using the cDNA microarray representing 27,648 genes, ii) To verify the genes for their low expression in 23 normal tissues by northern-blotting, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 262 cases of non-small cell lung cancers (NSCLCs), iv) To verify whether they are essential for the growth of cancer cells by siRNAs, v) To do immunoprecipitation assays and mass-spectrometric analysis to identify their interacting proteins in cancer cells, and screening of cell-permeable peptides that could inhibit the protein-protein interaction that is essential for carcinogenesis. Results: We identified 35 oncoproteins to be upregulated in the majority of lung cancers, and further selected CDCA5 (cell division cycle associated 5) as a good candidate. Tumor tissue microarray analysis of 262 NSCLC patients revealed that CDCA5 positivity was an independent prognostic factor. Suppression of CDCA5 expression with siRNAs inhibited the growth of lung cancer cells; concordantly, induction of exogenous expression of CDCA5 conferred growth-promoting activity in mammalian cells. We also found that extracellular signal-regulated kinase (ERK) kinase interacted with and phosphorylated CDCA5 at Serine 209 in vivo. Functional inhibition of the interaction between CDCA5 and ERK kinase by a cell-permeable peptide corresponding to a 20-amino-acid sequence part of CDCA5, which included the Serine 209 phosphorylation site by ERK, significantly reduced phosphorylation of CDCA5 and resulted in growth suppression of lung cancer cells. Conclusions: CDCA5 positivity should be useful as a novel prognostic biomarker in the clinic. Selective suppression of the ERK-CDCA5 pathway by cell-permeable peptide or small molecule-based drugs could be a promising strategy for cancer therapy.

scholarly journals Downregulation of c-fos gene transcription in cells transformed by E1A and cHa-ras oncogenes: a role of sustained activation of MAP/ERK kinase cascade and of inactive chromatin structure at c-fos promoter

Oncogene ◽  
2002 ◽  
Vol 21 (5) ◽  
pp. 719-730 ◽  
Author(s):  
Alexander N Kukushkin ◽  
Maria V Abramova ◽  
Svetlana B Svetlikova ◽  
Zalfia A Darieva ◽  
Tatiana V Pospelova ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Chromatin Structure ◽  
Kinase Cascade ◽  
Ras Oncogenes ◽  
Inactive Chromatin ◽  
Erk Kinase ◽  
Sustained Activation ◽  
In Cells

scholarly journals What is the physiological role of hypothalamic tanycytes in metabolism?

2021 ◽  
Author(s):  
Matei Bolborea ◽  
Fanny Langlet
Keyword(s):  
Energy Balance ◽  
Metabolic Disorders ◽  
Neural Circuits ◽  
Physiological Function ◽  
Physiological Role ◽  
Optimal Conditions ◽  
Age Related ◽  
New Research ◽  
Opening Up

In vertebrates, the energy balance process is tightly controlled by complex neural circuits that sense metabolic signals and adjust food intake and energy expenditure in line with the physiological requirements of optimal conditions. Within neural networks controlling energy balance, tanycytes are peculiar ependymoglial cells that are nowadays recognized as multifunctional players in the metabolic hypothalamus. However, the physiological function of hypothalamic tanycytes remains unclear, creating a number of ambiguities in the field. Here, we review data accumulated over the years that demonstrate the physiological function of tanycytes in the maintenance of metabolic homeostasis, opening up new research avenues. The presumed involvement of tanycytes in the pathophysiology of metabolic disorders and age-related neurodegenerative diseases will be finally discussed.

scholarly journals A Gene Expression High-Throughput Screen (GE-HTS) for Coordinated Detection of Functionally Similar Effectors in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3143
Author(s):  
Chaitra Rao ◽  
Dianna H. Huisman ◽  
Heidi M. Vieira ◽  
Danielle E. Frodyma ◽  
Beth K. Neilsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Natural Products ◽  
High Throughput ◽  
High Throughput Screening ◽  
Loss Of Function ◽  
Synthetic Lethal ◽  
Genome Wide ◽  
Pathway Activation ◽  
Kinase Suppressor Of Ras ◽  
Kinase Cascade

Genome-wide, loss-of-function screening can be used to identify novel vulnerabilities upon which specific tumor cells depend for survival. Functional Signature Ontology (FUSION) is a gene expression-based high-throughput screening (GE-HTS) method that allows researchers to identify functionally similar proteins, small molecules, and microRNA mimics, revealing novel therapeutic targets. FUSION uses cell-based high-throughput screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA libraries to identify putative protein targets and mechanisms of action (MoA) for several previously undescribed natural products. We have used FUSION to screen for functional analogues to Kinase suppressor of Ras 1 (KSR1), a scaffold protein downstream of Ras in the Raf-MEK-ERK kinase cascade, and biologically validated several proteins with functional similarity to KSR1. FUSION incorporates bioinformatics analysis that may offer higher resolution of the endpoint readout than other screens which utilize Boolean outputs regarding a single pathway activation (i.e., synthetic lethal and cell proliferation). Challenges associated with FUSION and other high-content genome-wide screens include variation, batch effects, and controlling for potential off-target effects. In this review, we discuss the efficacy of FUSION to identify novel inhibitors and oncogene-induced changes that may be cancer cell-specific as well as several potential pitfalls within FUSION and best practices to avoid them.

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