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ACS Chemical Biology Jan 2015Small molecule inhibitors of protein kinases are key tools for signal transduction research and represent a major class of targeted drugs. Recent developments in... (Review)
Review
Small molecule inhibitors of protein kinases are key tools for signal transduction research and represent a major class of targeted drugs. Recent developments in quantitative proteomics enable an unbiased view on kinase inhibitor selectivity and modes of action in the biological context. While chemical proteomics techniques utilizing quantitative mass spectrometry interrogate both target specificity and affinity in cellular extracts, proteome-wide phosphorylation analyses upon kinase inhibitor treatment identify signal transduction pathway and network regulation in an unbiased manner. Thus, critical information is provided to promote new insights into mechanisms of kinase signaling and their relevance for kinase inhibitor drug discovery.
Topics: Animals; Drug Discovery; Enzymes, Immobilized; Humans; Phosphorylation; Protein Binding; Protein Kinase Inhibitors; Protein Kinases; Proteomics; Signal Transduction; Small Molecule Libraries
PubMed: 25474541
DOI: 10.1021/cb5008794 -
Cell Structure and Function Apr 2018Protein kinases play pivotal roles in intracellular signal transduction, and dysregulation of kinases leads to pathological results such as malignant tumors. Kinase... (Review)
Review
Protein kinases play pivotal roles in intracellular signal transduction, and dysregulation of kinases leads to pathological results such as malignant tumors. Kinase activity has hitherto been measured by biochemical methods such as in vitro phosphorylation assay and western blotting. However, these methods are less useful to explore spatial and temporal changes in kinase activity and its cell-to-cell variation. Recent advances in fluorescent proteins and live-cell imaging techniques enable us to visualize kinase activity in living cells with high spatial and temporal resolutions. Several genetically encoded kinase activity reporters, which are based on the modes of action of kinase activation and phosphorylation, are currently available. These reporters are classified into single-fluorophore kinase activity reporters and Förster (or fluorescence) resonance energy transfer (FRET)-based kinase activity reporters. Here, we introduce the principles of genetically encoded kinase activity reporters, and discuss the advantages and disadvantages of these reporters.Key words: kinase, FRET, phosphorylation, KTR.
Topics: Biosensing Techniques; Fluorescence Resonance Energy Transfer; Genes, Reporter; Humans; Luminescent Proteins; Microscopy, Fluorescence; Protein Kinases
PubMed: 29553079
DOI: 10.1247/csf.18003 -
Mathematical Biosciences Apr 2015Protein kinases have been implicated in a number of diseases, where kinases participate many aspects that control cell growth, movement and death. The deregulated kinase... (Review)
Review
Protein kinases have been implicated in a number of diseases, where kinases participate many aspects that control cell growth, movement and death. The deregulated kinase activities and the knowledge of these disorders are of great clinical interest of drug discovery. The most critical issue is the development of safe and efficient disease diagnosis and treatment for less cost and in less time. It is critical to develop innovative approaches that aim at the root cause of a disease, not just its symptoms. Bioinformatics including genetic, genomic, mathematics and computational technologies, has become the most promising option for effective drug discovery, and has showed its potential in early stage of drug-target identification and target validation. It is essential that these aspects are understood and integrated into new methods used in drug discovery for diseases arisen from deregulated kinase activity. This article reviews bioinformatics techniques for protein kinase data management and analysis, kinase pathways and drug targets and describes their potential application in pharma ceutical industry.
Topics: Computational Biology; Drug Delivery Systems; Drug Discovery; Humans; Metabolic Networks and Pathways; Models, Biological; Protein Kinase Inhibitors; Protein Kinases
PubMed: 25656386
DOI: 10.1016/j.mbs.2015.01.010 -
International Journal of Molecular... Sep 2016Pancreatic β-cell failure and death is considered to be one of the main factors responsible for type 2 diabetes. It is caused by, in addition to hyperglycemia, chronic... (Review)
Review
Pancreatic β-cell failure and death is considered to be one of the main factors responsible for type 2 diabetes. It is caused by, in addition to hyperglycemia, chronic exposure to increased concentrations of fatty acids, mainly saturated fatty acids. Molecular mechanisms of apoptosis induction by saturated fatty acids in β-cells are not completely clear. It has been proposed that kinase signaling could be involved, particularly, c-Jun N-terminal kinase (JNK), protein kinase C (PKC), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and Akt kinases and their pathways. In this review, we discuss these kinases and their signaling pathways with respect to their possible role in apoptosis induction by saturated fatty acids in pancreatic β-cells.
Topics: Animals; Apoptosis; Endoplasmic Reticulum Stress; Fatty Acids; Humans; Insulin-Secreting Cells; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Protein Kinase C; Proto-Oncogene Proteins c-akt; p38 Mitogen-Activated Protein Kinases
PubMed: 27626409
DOI: 10.3390/ijms17091400 -
International Journal of Molecular... Mar 2019Protein phosphorylation regulated by protein kinases, as well as their dephosphorylation, is one of the most common post-translational modifications, and plays important... (Review)
Review
Protein phosphorylation regulated by protein kinases, as well as their dephosphorylation, is one of the most common post-translational modifications, and plays important roles in physiological activities, such as intracellular signal communications, gene transcription, cell proliferation and apoptosis. Over-expression of protein kinases is closely associated with various diseases. Consequently, accurate detection of protein kinases activities and their relevant inhibitors screening is critically important, not only to the biochemical research, but also to the clinical diagnosis and therapy. Nanomaterials, taking advantage of large surface areas, as well as excellent electrical, catalytic, magnetic and optical properties, have been utilized as target concentrators, recognition components, signal transducer or amplification elements in protein kinase related assays. This review summarizes the recent representative works to highlight the applications of nanomaterials in different biosensor technologies for protein kinases activities detection and their inhibitors screening. First, different nanomaterials developed for phosphoprotein/phosphopeptide enrichment and phosphate recognition are introduced. Next, representative works are selected that mainly focus on the utilization of nanomaterials as signal transducer or amplification elements in various protein kinases sensing platforms, such as electrochemical, colorimetric, fluorescent, and mass spectroscopy-based approaches. Finally, the major challenges and perspectives of nanomaterials being applied in protein kinases related assays are discussed.
Topics: Animals; Biosensing Techniques; Colorimetry; Electrochemical Techniques; Enzyme Activation; Humans; Nanostructures; Nanotechnology; Phosphates; Phosphoproteins; Phosphorylation; Photochemistry; Protein Binding; Protein Kinases; Signal Transduction
PubMed: 30901923
DOI: 10.3390/ijms20061440 -
The Enzymes 2023Discovery of the class of protein kinase now dubbed a mitogen (or messenger)-activated protein kinase (MAPK) is an illustrative example of how disparate lines of...
Discovery of the class of protein kinase now dubbed a mitogen (or messenger)-activated protein kinase (MAPK) is an illustrative example of how disparate lines of investigation can converge and reveal an enzyme family universally conserved among eukaryotes, from single-celled microbes to humans. Moreover, elucidation of the circuitry controlling MAPK function defined a now overarching principle in enzyme regulation-the concept of an activation cascade mediated by sequential phosphorylation events. Particularly ground-breaking for this field of exploration were the contributions of genetic approaches conducted using several model organisms, but especially the budding yeast Saccharomyces cerevisiae. Notably, examination of how haploid yeast cells respond to their secreted peptide mating pheromones was crucial in pinpointing genes encoding MAPKs and their upstream activators. Fully contemporaneous biochemical analysis of the activities elicited upon stimulation of mammalian cells by insulin and other growth- and differentiation-inducing factors lead eventually to the demonstration that components homologous to those in yeast were involved. Continued studies of these pathways in yeast were integral to other foundational discoveries in MAPK signaling, including the roles of tethering, scaffolding and docking interactions.
Topics: Animals; Humans; Saccharomyces cerevisiae; Mitogen-Activated Protein Kinases; Signal Transduction; Phosphorylation; Protein Kinases; Mammals
PubMed: 37945169
DOI: 10.1016/bs.enz.2023.07.001 -
Molecular Cell Jan 2024Cellular homeostasis is continuously challenged by environmental cues and cellular stress conditions. In their defense, cells need to mount appropriate stress responses... (Review)
Review
Cellular homeostasis is continuously challenged by environmental cues and cellular stress conditions. In their defense, cells need to mount appropriate stress responses that, dependent on the cellular context, signaling intensity, and duration, may have diverse outcomes. The stress- and mitogen-activated protein kinase (SAPK/MAPK) system consists of well-characterized signaling cascades that sense and transduce an array of different stress stimuli into biological responses. However, the physical and chemical nature of stress signals and how these are sensed by individual upstream MAP kinase kinase kinases (MAP3Ks) remain largely ambiguous. Here, we review the existing knowledge of how individual members of the large and diverse group of MAP3Ks sense specific stress signals through largely non-redundant mechanisms. We emphasize the large knowledge gaps in assigning function and stress signals for individual MAP3K family members and touch on the potential of targeting this class of proteins for clinical benefit.
Topics: Animals; MAP Kinase Kinase Kinases; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Signal Transduction; Phosphorylation; p38 Mitogen-Activated Protein Kinases; Calcium-Calmodulin-Dependent Protein Kinases; Mammals
PubMed: 38118452
DOI: 10.1016/j.molcel.2023.11.028 -
Essays in Biochemistry Sep 2022Plant immunity is crucial to plant health but comes at an expense. For optimal plant growth, tight immune regulation is required to prevent unnecessary rechannelling of... (Review)
Review
Plant immunity is crucial to plant health but comes at an expense. For optimal plant growth, tight immune regulation is required to prevent unnecessary rechannelling of valuable resources. Pattern- and effector-triggered immunity (PTI/ETI) represent the two tiers of immunity initiated after sensing microbial patterns at the cell surface or pathogen effectors secreted into plant cells, respectively. Recent evidence of PTI-ETI cross-potentiation suggests a close interplay of signalling pathways and defense responses downstream of perception that is still poorly understood. This review will focus on controls on plant immunity through phosphorylation, a universal and key cellular regulatory mechanism. Rather than a complete overview, we highlight "what's new in protein kinase/phosphatase signalling" in the immunity field. In addition to phosphoregulation of components in the pattern recognition receptor (PRR) complex, we will cover the actions of the major immunity-relevant intracellular protein kinases/phosphatases in the 'signal relay', namely calcium-regulated kinases (e.g. calcium-dependent protein kinases, CDPKs), mitogen-activated protein kinases (MAPKs), and various protein phosphatases. We discuss how these factors define a phosphocode that generates cellular decision-making 'logic gates', which contribute to signalling fidelity, amplitude, and duration. To underscore the importance of phosphorylation, we summarize strategies employed by pathogens to subvert plant immune phosphopathways. In view of recent game-changing discoveries of ETI-derived resistosomes organizing into calcium-permeable pores, we speculate on a possible calcium-regulated phosphocode as the mechanistic control of the PTI-ETI continuum.
Topics: Calcium; Mitogen-Activated Protein Kinases; Phosphoprotein Phosphatases; Plant Immunity; Protein Kinases; Receptors, Pattern Recognition
PubMed: 35723080
DOI: 10.1042/EBC20210088 -
Methods in Molecular Biology (Clifton,... 2017A powerful interplay exists between the recognition of gene families, sensitive techniques in proteomics, and the interrogation of protein function using chemical... (Review)
Review
A powerful interplay exists between the recognition of gene families, sensitive techniques in proteomics, and the interrogation of protein function using chemical probes. The most prominent methods, such as affinity capture, activity-based protein profiling and photoaffinity labeling, are extensively reviewed in the literature. Here we briefly review additional methods developed in the past 15 years. These include "stability proteomics" methods such as proteomically analyzed cellular thermal shift assays and the use of chemical oxidation as a probe of structure, the use of multiple bead-linked kinase inhibitors to analyze inhibitor specificities, and advances in the use of proteolysis-targeting chimeras for selective protein elimination.
Topics: Antineoplastic Agents; Biological Assay; Drug Discovery; Gene Expression; Humans; K562 Cells; Neoplasm Proteins; Oxidation-Reduction; Protein Denaturation; Protein Kinase Inhibitors; Protein Kinases; Protein Stability; Proteomics; Thermodynamics
PubMed: 27807827
DOI: 10.1007/978-1-4939-6539-7_2 -
Current Medicinal Chemistry 2023Protein kinases modulate the structure and function of proteins by adding phosphate groups to threonine, tyrosine, and serine residues. The phosphorylation process... (Review)
Review
Protein kinases modulate the structure and function of proteins by adding phosphate groups to threonine, tyrosine, and serine residues. The phosphorylation process mediated by the kinases regulates several physiological processes, while their overexpression results in the development of chronic diseases, including cancer. Targeting of receptor tyrosine kinase pathways results in the inhibition of angiogenesis and cell proliferation that validates kinases as a key target in the management of aggressive cancers. As such, the identification of protein kinase inhibitors revolutionized the contemporary anticancer therapy by inducing a paradigm shift in the management of disease pathogenesis. Contemporary drug design programs focus on a broad range of kinase targets for the development of novel pharmacophores to manage the overexpression of kinases and their pathophysiology in cancer pathogenesis. In this review, we present the emerging trends in the development of rationally designed molecular inhibitors of kinases over the last five years (2016-2021) and their incipient role in the development of impending anticancer pharmaceuticals.
Topics: Humans; Neoplasms; Receptor Protein-Tyrosine Kinases; Protein Kinases; Protein Kinase Inhibitors; Phosphorylation
PubMed: 34766883
DOI: 10.2174/0929867328666211111161811