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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 -
Biochemical Society Transactions Feb 2023Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a serine/threonine-protein kinase, that is involved in maintaining various physiological and cellular... (Review)
Review
Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a serine/threonine-protein kinase, that is involved in maintaining various physiological and cellular processes within the cell that regulate energy homeostasis and cell growth. CaMKK2 regulates glucose metabolism by the activation of downstream kinases, AMP-activated protein kinase (AMPK) and other calcium/calmodulin-dependent protein kinases. Consequently, its deregulation has a role in multiple human metabolic diseases including obesity and cancer. Despite the importance of CaMKK2, its signalling pathways and pathological mechanisms are not completely understood. Recent work has been aimed at broadening our understanding of the biological functions of CaMKK2. These studies have uncovered new interaction partners that have led to the description of new functions that include lipogenesis and Golgi vesicle trafficking. Here, we review recent insights into the role of CaMKK2 in membrane trafficking mechanisms and discuss the functional implications in a cellular context and for disease.
Topics: Humans; Calcium; Protein Serine-Threonine Kinases; AMP-Activated Protein Kinases; Signal Transduction; Cell Proliferation; Calcium-Calmodulin-Dependent Protein Kinase Kinase
PubMed: 36815702
DOI: 10.1042/BST20220833 -
International Journal of Molecular... Aug 2017Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in... (Review)
Review
Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in almost all physiological and pathological conditions. Mitosis is a key event during the cell cycle, in which the cell divides into two daughter cells. Autophagy is a process in which the cell digests its own cellular contents. Although autophagy regulation has mainly been studied in asynchronous cells, increasing evidence indicates that autophagy is in fact tightly regulated in mitosis. Here in this review, we will discuss kinases that were originally identified to be involved in only one of either mitosis or autophagy, but were later found to participate in both processes, such as CDKs (cyclin-dependent kinases), Aurora kinases, PLK-1 (polo-like kinase 1), BUB1 (budding uninhibited by benzimidazoles 1), MAPKs (mitogen-activated protein kinases), mTORC1 (mechanistic target of rapamycin complex 1), AMPK (AMP-activated protein kinase), PI3K (phosphoinositide-3 kinase) and protein kinase B (AKT). By focusing on kinases involved in both autophagy and mitosis, we will get a more comprehensive understanding about the reciprocal regulation between the two key cellular events, which will also shed light on their related therapeutic investigations.
Topics: Animals; Autophagy; Humans; Mitosis; Protein Kinases
PubMed: 28858266
DOI: 10.3390/ijms18091884 -
Ageing Research Reviews Mar 2023Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. Motor impairment seen in PD is associated with dopaminergic neurotoxicity... (Review)
Review
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. Motor impairment seen in PD is associated with dopaminergic neurotoxicity in the striatum, and dopaminergic neuronal death in the substantia nigra pars compacta. Cell death has a significant effect on the development and progression of PD. Extensive research over the last few decades has unveiled new regulated cell death (RCD) mechanisms that are not dependent on apoptosis such as necroptosis, ferroptosis, and others. In this review, we will overview the mechanistic pathways of different types of RCD. Unlike accidental cell death, RCD subroutines can be regulated and the RCD-associated kinases are potential druggable targets. Hence, we will address an overview and analysis of different kinases regulating apoptosis such as receptor-interacting protein kinase 1 (RIPK-1), RIPK3, mixed lineage kinase (MLK), Ataxia telangiectasia muted (ATM), cyclin-dependent kinase (CDK), death-associated protein kinase 1 (DAPK1), Apoptosis-signaling kinase-1 (ASK-1), and Leucine-rich repeat kinase-2 (LRRK2). In addition to the role of RIPK1, RIPK3, and Mixed Lineage Kinase Domain like Pseudokinase (MLKL) in necroptosis. We also overview functions of AMP-kinase (AMPK), protein kinase C (PKC), RIPK3, and ATM in ferroptosis. We will recap the anti-apoptotic, anti-necroptotic, and anti-ferroptotic effects of different kinase inhibitors in different models of PD. Finally, we will discuss future challenges in the repositioning of kinase inhibitors in PD. In conclusion, this review kicks-start targeting RCD from a kinases perspective, opening novel therapeutic disease-modifying therapeutic avenues for PD.
Topics: Humans; Parkinson Disease; Protein Kinases; Apoptosis; Cell Death; Neurodegenerative Diseases
PubMed: 36608709
DOI: 10.1016/j.arr.2022.101841 -
Biochimica Et Biophysica Acta Oct 2015Protein phosphorylation is a key reaction in the regulation of cellular events and is catalysed by over 500 protein kinases in humans. The activities of protein kinases... (Review)
Review
Protein phosphorylation is a key reaction in the regulation of cellular events and is catalysed by over 500 protein kinases in humans. The activities of protein kinases are strictly controlled through a diverse set of mechanisms. Structural studies have shown that the conformation adopted by kinases in their active state is highly similar, whereas inactive kinases can adopt a variety of conformations. Many kinases are maintained in a catalytically inactive state through autoinhibition. This involves a conformation of the kinase active site that is unable to support catalysis and requires activation through a signal such as binding of a regulatory protein. In this review, we briefly summarise some of the well-established autoinhibitory mechanisms and then focus on a relatively unexplored mode of autoinhibition that was first discovered in the Nek family of kinases and is also relevant to IRE1. This involves a tyrosine side-chain that blocks the active site and which must undergo a conformational change to enable kinase activity. We have termed this the Tyr-down autoinhibitory mechanism. We summarise the evidence for this mechanism and describe its role in kinase inhibitor design. Finally, we survey the kinome to identify other kinases with the potential to be governed by an autoinhibitory Tyr-down mechanism. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.
Topics: Catalysis; Catalytic Domain; Humans; Phosphorylation; Protein Conformation; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship; src-Family Kinases
PubMed: 25936518
DOI: 10.1016/j.bbapap.2015.04.025 -
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 -
Chemical Biology & Drug Design Dec 2022Protein kinases are key regulators of cellular signaling and play a critical role in oncogenesis. Inhibitors of protein kinases are pursued by both industry and academia... (Review)
Review
Protein kinases are key regulators of cellular signaling and play a critical role in oncogenesis. Inhibitors of protein kinases are pursued by both industry and academia as a promising target for cancer therapy. Within the protein kinases, the ATP site has produced more than 40 FDA-approved drugs. The ATP site is broadly composed of a hinge region, gatekeeper residues, DFG-loop, ribose pocket, and other hydrophobic regions. The hinge region in the ATP site can be used for designing potent inhibitors. In this review, we discuss some representative studies that will highlight the interactions of heterocyclic compounds with hinge regions of different kinases like BRAF kinase, EGRF kinase, MAP kinase, and Mps1 kinase.
Topics: Protein Kinase Inhibitors; Chemistry, Pharmaceutical; Protein Kinases; Adenosine Triphosphate
PubMed: 35112799
DOI: 10.1111/cbdd.14024 -
Biochemical Pharmacology Dec 2017Neuroinflammation is mediated by resident central nervous system glia, neurons, peripherally derived immune cells, blood-brain barrier, and inflammatory mediators... (Review)
Review
Neuroinflammation is mediated by resident central nervous system glia, neurons, peripherally derived immune cells, blood-brain barrier, and inflammatory mediators secreted from these cells. Neuroinflammation has been implicated in stroke and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Protein kinases have been one of the most exploited therapeutic targets in the current pharmacological research, especially in studies on cancer and inflammation. To date, 32 small-molecule protein kinase inhibitors have been approved by the United States Food and Drug Administration for the treatment of cancer and inflammation. However, there is no drug effectively targeting neuroinflammation and/or neurodegenerative diseases. Recent studies have advanced several protein kinases as important drug targets in neuroinflammation and/or neurodegenerative diseases. Here, we review emerging protein kinases potentially involved in neuroinflammation and subsequent neurodegenerative diseases.
Topics: Central Nervous System Diseases; Gene Expression Regulation, Enzymologic; Humans; Inflammation; Microglia; Protein Kinases
PubMed: 28684305
DOI: 10.1016/j.bcp.2017.06.137 -
Current Drug Targets 2019Protein kinases play critical roles in the control of cell growth, proliferation, migration, and angiogenesis, through their catalytic activity. Over the past years,... (Review)
Review
Protein kinases play critical roles in the control of cell growth, proliferation, migration, and angiogenesis, through their catalytic activity. Over the past years, numerous protein kinase inhibitors have been identified and are being successfully used clinically. Traditional Chinese medicine (TCM) represents a large class of bioactive substances, and some of them display anticancer activity via inhibiting protein kinases signal pathway. Some of the TCM have been used to treat tumors clinically in China for many years. The p38mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase, serine/threonine-specific protein kinases (PI3K/AKT/mTOR), and extracellular signal-regulated kinases (ERK) pathways are considered important signals in cancer cell development. In the present article, the recent progress of TCM that exhibited significant inhibitory activity towards a range of protein kinases is discussed. The clinical efficacy of TCM with inhibitory effects on protein kinases in treating a tumor is also presented. The article also discussed the prospects and problems in the development of anticancer agents with TCM.
Topics: Antineoplastic Agents; Drug Development; Humans; Medicine, Chinese Traditional; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 31376819
DOI: 10.2174/1389450120666190802125959 -
Trends in Biochemical Sciences Jan 2019The recent implication of the cell death pathway, necroptosis, in innate immunity and a range of human pathologies has led to intense interest in the underlying... (Review)
Review
The recent implication of the cell death pathway, necroptosis, in innate immunity and a range of human pathologies has led to intense interest in the underlying molecular mechanism. Unlike the better-understood apoptosis pathway, necroptosis is a caspase-independent pathway that leads to cell lysis and release of immunogens downstream of death receptor and Toll-like receptor (TLR) ligation. Here we review the role of recent structural studies of the core machinery of the pathway, the protein kinases receptor-interacting protein kinase (RIPK)1 and RIPK3, and the terminal effector, the pseudokinase mixed lineage kinase domain-like protein (MLKL), in shaping our mechanistic understanding of necroptotic signaling. Structural studies have played a key role in establishing models that describe MLKL's transition from a dormant monomer to a killer oligomer and revealing important interspecies differences.
Topics: Cell Death; Humans; Protein Conformation; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 30509860
DOI: 10.1016/j.tibs.2018.11.002