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The Journal of Biological Chemistry Aug 2022Protein kinases are key components in cellular signaling pathways as they carry out the phosphorylation of proteins, primarily on Ser, Thr, and Tyr residues. The... (Review)
Review
Protein kinases are key components in cellular signaling pathways as they carry out the phosphorylation of proteins, primarily on Ser, Thr, and Tyr residues. The catalytic activity of protein kinases is regulated, and they can be thought of as molecular switches that are controlled through protein-protein interactions and post-translational modifications. Protein kinases exhibit diverse structural mechanisms of regulation and have been fascinating subjects for structural biologists from the first crystal structure of a protein kinase over 30 years ago, to recent insights into kinase assemblies enabled by the breakthroughs in cryo-EM. Protein kinases are high-priority targets for drug discovery in oncology and other disease settings, and kinase inhibitors have transformed the outcomes of specific groups of patients. Most kinase inhibitors are ATP competitive, deriving potency by occupying the deep hydrophobic pocket at the heart of the kinase domain. Selectivity of inhibitors depends on exploiting differences between the amino acids that line the ATP site and exploring the surrounding pockets that are present in inactive states of the kinase. More recently, allosteric pockets outside the ATP site are being targeted to achieve high selectivity and to overcome resistance to current therapeutics. Here, we review the key regulatory features of the protein kinase family, describe the different types of kinase inhibitors, and highlight examples where the understanding of kinase regulatory mechanisms has gone hand in hand with the development of inhibitors.
Topics: Adenosine Triphosphate; Drug Discovery; Humans; Phosphorylation; Protein Binding; Protein Kinase Inhibitors; Protein Kinases
PubMed: 35830914
DOI: 10.1016/j.jbc.2022.102247 -
Trends in Pharmacological Sciences Nov 2019Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary... (Review)
Review
Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary kinase classes, the eukaryotic protein kinases (ePKs) and the atypical protein kinases (aPKs), and provides a structure-centered comparison of their sequences, structures, hydrophobic spines, mutation and SNP hotspots, and inhibitor interaction patterns. Despite the limited sequence similarity between these two classes, atypical kinases commonly share the archetypical kinase fold but lack conserved eukaryotic kinase motifs and possess altered hydrophobic spines. Furthermore, atypical kinase inhibitors explore only a limited number of binding modes both inside and outside the orthosteric binding site. The distribution of genetic variations in both classes shows multiple ways they can interfere with kinase inhibitor binding. This multilayered review provides a research framework bridging the eukaryotic and atypical kinase classes.
Topics: Amino Acid Sequence; Antineoplastic Agents; Binding Sites; Humans; Models, Molecular; Neoplasms; Polymorphism, Single Nucleotide; Protein Conformation, beta-Strand; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship
PubMed: 31677919
DOI: 10.1016/j.tips.2019.09.002 -
Vascular Pharmacology Dec 2023Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in the Western world. Multiple molecular and cellular processes underpinning the... (Review)
Review
Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in the Western world. Multiple molecular and cellular processes underpinning the pathogenesis of CVD are regulated by the zinc finger transcription factor and product of an immediate-early gene, early growth response-1 (Egr-1). Egr-1 regulates multiple pro-inflammatory processes that underpin the manifestation of CVD. The activity of Egr-1 itself is influenced by a range of post-translational modifications including sumoylation, ubiquitination and acetylation. Egr-1 also undergoes phosphorylation by protein kinases, such as extracellular-signal regulated kinase (ERK) which is itself phosphorylated by MEK. This article reviews recent progress on the MEK-ERK-Egr-1 cascade, notably regulation in conjunction with factors and agents such as TET2, TRIB2, MIAT, SphK1, cAMP, teneligliptin, cholinergic drugs, red wine and flavonoids, wogonin, febuxostat, docosahexaenoic acid and AT1R blockade. Such insights should provide new opportunity for therapeutic intervention in CVD.
Topics: Humans; Extracellular Signal-Regulated MAP Kinases; Cardiovascular Diseases; Transcription Factors; Phosphorylation; Mitogen-Activated Protein Kinase Kinases; Calcium-Calmodulin-Dependent Protein Kinases
PubMed: 37734428
DOI: 10.1016/j.vph.2023.107232 -
Biomolecules Jul 2022The discovery of protein kinase playing key roles in cancer formation and progression has triggered great interest and stimulated intense research on signaling pathways...
The discovery of protein kinase playing key roles in cancer formation and progression has triggered great interest and stimulated intense research on signaling pathways to develop targeted treatments, as well as to identify prognostic and predictive biomarkers [...].
Topics: Biomarkers; Humans; Neoplasms; Phosphorylation; Protein Kinases; Signal Transduction
PubMed: 36008930
DOI: 10.3390/biom12081036 -
Molecular Cancer Feb 2018The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated... (Review)
Review
The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.
Topics: Animals; Humans; Molecular Structure; Neoplasms; Protein Kinase Inhibitors; Protein Kinases
PubMed: 29455673
DOI: 10.1186/s12943-018-0804-2 -
Cell Structure and Function 2015Checkpoint kinase 1 (Chk1) is a conserved protein kinase central to the cell-cycle checkpoint during DNA damage response (DDR). Until recently, ATR, a protein kinase... (Review)
Review
Checkpoint kinase 1 (Chk1) is a conserved protein kinase central to the cell-cycle checkpoint during DNA damage response (DDR). Until recently, ATR, a protein kinase activated in response to DNA damage or stalled replication, has been considered as the sole regulator of Chk1. Recent progress, however, has led to the identification of additional protein kinases involved in Chk1 phosphorylation, affecting the subcellular localization and binding partners of Chk1. In fact, spatio-temporal regulation of Chk1 is of critical importance not only in the DDR but also in normal cell-cycle progression. In due course, many potent inhibitors targeted to Chk1 have been developed as anticancer agents and some of these inhibitors are currently in clinical trials. In this review, we summarize the current knowledge of Chk1 regulation by phosphorylation.
Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Checkpoint Kinase 1; Cyclin-Dependent Kinases; Humans; Phosphorylation; Protein Kinases; Serine
PubMed: 25748360
DOI: 10.1247/csf.14017 -
International Journal of Molecular... Mar 2022Mitogen-activated protein kinases (MAPKs) form tightly controlled signaling cascades that play essential roles in plant growth, development, and defense response.... (Review)
Review
Mitogen-activated protein kinases (MAPKs) form tightly controlled signaling cascades that play essential roles in plant growth, development, and defense response. However, the molecular mechanisms underlying MAPK cascades are still very elusive, largely because of our poor understanding of how they relay the signals. The MAPK cascade is composed of MAPK, MAPKK, and MAPKKK. They transfer signals through the phosphorylation of MAPKKK, MAPKK, and MAPK in turn. MAPKs are organized into a complex network for efficient transmission of specific stimuli. This review summarizes the research progress in recent years on the classification and functions of MAPK cascades under various conditions in plants, especially the research status and general methods available for identifying MAPK substrates, and provides suggestions for future research directions.
Topics: MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Plant Development
PubMed: 35269886
DOI: 10.3390/ijms23052744 -
International Journal of Molecular... Aug 2018Alongside Liver kinase B1 (LKB1) and Ca/Calmodulin-dependent protein kinase kinase 2 (CaMKK2), Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) has been... (Review)
Review
Alongside Liver kinase B1 (LKB1) and Ca/Calmodulin-dependent protein kinase kinase 2 (CaMKK2), Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) has been suggested as a direct upstream kinase of AMP-activated protein kinase (AMPK). Several subsequent studies have reported on the TAK1-AMPK relationship, but the interpretation of the respective data has led to conflicting views. Therefore, to date the acceptance of TAK1 as a genuine AMPK kinase is lagging behind. This review provides with argumentation, whether or not TAK1 functions as a direct upstream kinase of AMPK. Several specific open questions that may have precluded the consensus are discussed based on available data. In brief, TAK1 can function as direct AMPK upstream kinase in specific contexts and in response to a subset of TAK1 activating stimuli. Further research is needed to define the intricate signals that are conditional for TAK1 to phosphorylate and activate AMPKα at T172.
Topics: AMP-Activated Protein Kinase Kinases; Animals; Enzyme Activation; Humans; MAP Kinase Kinase Kinases; Models, Molecular; Phosphorylation; Protein Kinases
PubMed: 30111748
DOI: 10.3390/ijms19082412 -
Mitogen-Activated Protein Kinase and Exploratory Nuclear Receptor Crosstalk in Cancer Immunotherapy.International Journal of Molecular... Sep 2023The three major mitogen-activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK/SAPK) are upstream regulators of the nuclear receptor superfamily (NRSF). These... (Review)
Review
The three major mitogen-activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK/SAPK) are upstream regulators of the nuclear receptor superfamily (NRSF). These ligand-activated transcription factors are divided into subclasses comprising receptors for endocrine hormones, metabolic compounds (e.g., vitamins, diet), xenobiotics, and mediators released from host immune reactions such as tissue injury and inflammation. These internal and external cues place the NRSF at the frontline as sensors and translators of information from the environment towards the genome. For most of the former "orphan" receptors, physiological and synthetic ligands have been identified, opening intriguing opportunities for combination therapies with existing cancer medications. Hitherto, only preclinical data are available, warranting further validation in clinical trials in patients. The current review summarized the existing literature covering the expression and function of NRSF subclasses in human solid tumors and hematopoietic malignancies and their modulatory effects on innate (e.g., macrophages, dendritic cells) and adaptive (i.e., T cell subsets) immune cells, encouraging mechanistic and pharmacological studies in combination with current clinically approved therapeutics against immune checkpoint molecules (e.g., PD1).
Topics: Humans; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases; Receptors, Cytoplasmic and Nuclear; Immunotherapy; Neoplasms
PubMed: 37833991
DOI: 10.3390/ijms241914546 -
Marine Drugs Sep 2019Autophagy is a lysosomal pathway that degrades and recycles unused or dysfunctional cell components as well as toxic cytosolic materials. Basal autophagy favors cell... (Review)
Review
Autophagy is a lysosomal pathway that degrades and recycles unused or dysfunctional cell components as well as toxic cytosolic materials. Basal autophagy favors cell survival. However, the aberrant regulation of autophagy can promote pathological conditions. The autophagy pathway is regulated by several cell-stress and cell-survival signaling pathways that can be targeted for the purpose of disease control. In experimental models of disease, the carotenoid astaxanthin has been shown to modulate autophagy by regulating signaling pathways, including the AMP-activated protein kinase (AMPK), cellular homolog of murine thymoma virus akt8 oncogene (Akt), and mitogen-activated protein kinase (MAPK), such as c-Jun N-terminal kinase (JNK) and p38. Astaxanthin is a promising therapeutic agent for the treatment of a wide variety of diseases by regulating autophagy.
Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Humans; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases; Signal Transduction; Xanthophylls; p38 Mitogen-Activated Protein Kinases
PubMed: 31547619
DOI: 10.3390/md17100546