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Cellular and Molecular Life Sciences :... Sep 2023The receptor interacting protein kinases (RIPK) are a family of serine/threonine kinases that are involved in the integration of various stress signals. In response to... (Review)
Review
The receptor interacting protein kinases (RIPK) are a family of serine/threonine kinases that are involved in the integration of various stress signals. In response to several extracellular and/or intracellular stimuli, RIP kinases engage signaling cascades leading to the activation of NF-κB and mitogen-activated protein kinases, cell death, inflammation, differentiation and Wnt signaling and can have kinase-dependent and kinase-independent functions. Although it was previously suggested that seven RIPKs are part of the RIPK family, phylogenetic analysis indicates that there are only five genuine RIPKs. RIPK1 and RIPK3 are mainly involved in controlling and executing necroptosis in keratinocytes, while RIPK4 controls proliferation and differentiation of keratinocytes and thereby can act as a tumor suppressor in skin. Therefore, in this review we summarize and discuss the functions of RIPKs in skin homeostasis as well as the signaling pathways involved.
Topics: Phylogeny; Skin; Keratinocytes; Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases
PubMed: 37688617
DOI: 10.1007/s00018-023-04917-2 -
International Journal of Molecular... Apr 2024Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate... (Review)
Review
Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate signaling cascades, which converge on mitochondria and maintain the function of the organelles, which is critical for cell survival. The signaling cascades include not only extracellular molecules that activate sarcolemmal receptor-dependent or -independent protein kinases that signal at the plasma membrane or in the cytosol, but also involve kinases, which are located to or within mitochondria, phosphorylate mitochondrial target proteins, and thereby modify, e.g., respiration, the generation of reactive oxygen species, calcium handling, mitochondrial dynamics, mitophagy, or apoptosis. In the present review, we give a personal and opinionated overview of selected protein kinases, localized to/within myocardial mitochondria, and summarize the available data on their role in myocardial ischemia/reperfusion injury and protection from it. We highlight the regulation of mitochondrial function by these mitochondrial protein kinases.
Topics: Humans; Signal Transduction; Animals; Myocardial Reperfusion Injury; Mitochondria, Heart; Protein Kinases; Reactive Oxygen Species; Mitochondria
PubMed: 38674076
DOI: 10.3390/ijms25084491 -
Pharmacological Research Aug 2023Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic... (Review)
Review
Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic disorders and protein kinase antagonists have become an important drug target. Although the efficacy of imatinib in the treatment of chronic myelogenous leukemia in the United States in 2001 was the main driver of protein kinase inhibitor drug discovery, this was preceded by the approval of fasudil (a ROCK antagonist) in Japan in 1995 for the treatment of cerebral vasospasm. There are 21 small molecule protein kinase inhibitors that are approved in China, Japan, Europe, and South Korea that are not approved in the United Sates and 75 FDA-approved inhibitors in the United States. Of the 21 agents, eleven target receptor protein-tyrosine kinases, eight inhibit nonreceptor protein-tyrosine kinases, and two block protein-serine/threonine kinases. All 21 drugs are orally bioavailable or topically effective. Of the non-FDA approved drugs, sixteen are prescribed for the treatment of neoplastic diseases, three are directed toward inflammatory disorders, one is used for glaucoma, and fasudil is used in the management of vasospasm. The leading targets of kinase inhibitors approved by both international regulatory agencies and by the FDA are members of the EGFR family, the VEGFR family, and the JAK family. One-third of the 21 internationally approved drugs are not compliant with Lipinski's rule of five for orally bioavailable drugs. The rule of five relies on four parameters including molecular weight, number of hydrogen bond donors and acceptors, and the Log of the partition coefficient.
Topics: United States; Humans; Protein Kinase Inhibitors; Neoplasms; Protein Serine-Threonine Kinases; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Protein Kinases; Antineoplastic Agents
PubMed: 37454916
DOI: 10.1016/j.phrs.2023.106847 -
International Journal of Molecular... Aug 2023Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The... (Review)
Review
Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor β (TGFβ) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways.
Topics: Humans; Pulmonary Arterial Hypertension; Endothelial Cells; Familial Primary Pulmonary Hypertension; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit
PubMed: 37628831
DOI: 10.3390/ijms241612653 -
DNA Repair Sep 2023Yeast Mec1, and its mammalian ortholog, Ataxia-Telangiectasia and Rad3-related, are giant protein kinases central to replication stress and double strand DNA break... (Review)
Review
Yeast Mec1, and its mammalian ortholog, Ataxia-Telangiectasia and Rad3-related, are giant protein kinases central to replication stress and double strand DNA break repair. Mec1, in complex with Ddc2, is a 'sensor' of single stranded DNA, and phosphorylates numerous cell cycle and DNA repair factors to enforce cell cycle arrest and facilitate repair. Over the last several years, new techniques - particularly in structural biology - have provided molecular mechanisms for Mec1 function. It is becoming increasingly clear how post-translational modification of Mec1 and its interaction partners modulates the DNA damage checkpoint. In this review, we summarise the most recent work unravelling Mec1 function in the DNA damage checkpoint and provide a molecular context for its regulation by phosphorylation.
Topics: Animals; Protein Serine-Threonine Kinases; Intracellular Signaling Peptides and Proteins; Cell Cycle Proteins; Saccharomyces cerevisiae Proteins; DNA Damage; Saccharomyces cerevisiae; Phosphorylation; Checkpoint Kinase 1; Checkpoint Kinase 2; Mammals
PubMed: 37480741
DOI: 10.1016/j.dnarep.2023.103543 -
Cell Death and Differentiation Jan 2024Mixed lineage kinase-like protein (MLKL) forms amyloid-like polymers to promote necroptosis; however, the mechanism through which these polymers trigger cell death is...
Mixed lineage kinase-like protein (MLKL) forms amyloid-like polymers to promote necroptosis; however, the mechanism through which these polymers trigger cell death is not clear. We have determined that activated MLKL translocates to the lysosomal membrane during necroptosis induction. The subsequent polymerization of MLKL induces lysosome clustering and fusion and eventual lysosomal membrane permeabilization (LMP). This LMP leads to the rapid release of lysosomal contents into the cytosol, resulting in a massive surge in cathepsin levels, with Cathepsin B (CTSB) as a significant contributor to the ensuing cell death as it cleaves many proteins essential for cell survival. Importantly, chemical inhibition or knockdown of CTSB protects cells from necroptosis. Furthermore, induced polymerization of the MLKL N-terminal domain (NTD) also triggers LMP, leading to CTSB release and subsequent cell death. These findings clearly establish the critical role of MLKL polymerization induced lysosomal membrane permeabilization (MPI-LMP) in the process of necroptosis.
Topics: Protein Kinases; Necroptosis; Polymerization; Lysosomes; Polymers; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37996483
DOI: 10.1038/s41418-023-01237-7 -
Neurobiology of Disease Oct 2023Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common...
Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common mechanism in epileptogenesis. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in various inflammation-related diseases. Our previous study demonstrated that Trpm2 knockout exhibits therapeutic effects on pilocarpine-induced glial activation and neuroinflammation. However, whether TRPM2 in microglia and astrocytes plays a common pathogenic role in this process and the underlying molecular mechanisms remained undetermined. Here, we demonstrate a previously unknown role for microglial TRPM2 in epileptogenesis. Trpm2 knockout in microglia attenuated kainic acid (KA)-induced glial activation, inflammatory cytokines production and hippocampal paroxysmal discharges, whereas Trpm2 knockout in astrocytes exhibited no significant effects. Furthermore, we discovered that these therapeutic effects were mediated by upregulated autophagy via the adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in microglia. Thus, our findings highlight an important deleterious role of microglial TRPM2 in temporal lobe epilepsy.
Topics: Humans; Microglia; AMP-Activated Protein Kinases; Neuroinflammatory Diseases; TRPM Cation Channels; TOR Serine-Threonine Kinases; Autophagy; Calcium Channels
PubMed: 37648036
DOI: 10.1016/j.nbd.2023.106273 -
Journal of Neurodevelopmental Disorders Mar 2024Cyclic adenosine 3', 5' monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of... (Review)
Review
Cyclic adenosine 3', 5' monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of physiological processes including gene transcription, metabolism, and synaptic plasticity. Genomic sequencing studies have identified both germline and somatic variants of the catalytic and regulatory subunits of PKA in patients with metabolic and neurodevelopmental disorders. In this review we discuss the classical cAMP/PKA signaling pathway and the disease phenotypes that result from PKA variants. This review highlights distinct isoform-specific cognitive deficits that occur in both PKA catalytic and regulatory subunits, and how tissue-specific distribution of these isoforms may contribute to neurodevelopmental disorders in comparison to more generalized endocrine dysfunction.
Topics: Humans; Cyclic AMP-Dependent Protein Kinases; Phosphorylation; Signal Transduction; Nervous System Diseases
PubMed: 38481146
DOI: 10.1186/s11689-024-09525-0 -
Biomedicine & Pharmacotherapy =... Dec 2023DNMT1 (DNA methyltransferase 1) is the predominant member of the DNMT family and the most abundant DNMT in various cell types. It functions as a maintenance DNMT and is... (Review)
Review
DNMT1 (DNA methyltransferase 1) is the predominant member of the DNMT family and the most abundant DNMT in various cell types. It functions as a maintenance DNMT and is involved in various diseases, including cancer and nervous system diseases. Programmed cell death (PCD) is a fundamental mechanism that regulates cell proliferation and maintains the development and homeostasis of multicellular organisms. DNMT1 plays a regulatory role in various types of PCD, including apoptosis, autophagy, necroptosis, ferroptosis, and others. DNMT1 is closely associated with the development of various diseases by regulating key genes and pathways involved in PCD, including caspase 3/7 activities in apoptosis, Beclin 1, LC3, and some autophagy-related proteins in autophagy, glutathione peroxidase 4 (GPX4) and nuclear receptor coactivator 4 (NCOA4) in ferroptosis, and receptor-interacting protein kinase 1-receptor-interacting protein kinase 3-mixed lineage kinase domain-like protein (RIPK1-RIPK3-MLKL) in necroptosis. Our study summarizes the regulatory relationship between DNMT1 and different types of PCD in various diseases and discusses the potential of DNMT1 as a common regulatory hub in multiple types of PCD, offering a perspective for therapeutic approaches in disease.
Topics: Apoptosis; Ferroptosis; Protein Kinases; Transcription Factors; Humans; DNA (Cytosine-5-)-Methyltransferase 1
PubMed: 37871559
DOI: 10.1016/j.biopha.2023.115753 -
Frontiers in Bioscience (Landmark... Oct 2023Aging and related diseases significantly affect the health and happiness index around the world. Cellular senescence is the basis of physiological aging and is closely... (Review)
Review
Aging and related diseases significantly affect the health and happiness index around the world. Cellular senescence is the basis of physiological aging and is closely related to various senile diseases. AMP-activated protein kinase (AMPK) is associated with both the regulation of cellular energy metabolism and the regulation of cellular senescence. Another set of proteins, sirtuins, has also been demonstrated to play an important role in cell senescence. However, it is not clear how AMPK and sirtuins coordinate to regulate cellular senescence. Herein, we summarized the role of AMPK and sirtuins in regulating metabolism, repairing DNA damage, and even prolonging human life. We have provided a detailed explanation of the clinical trials relating to the AMPK and sirtuins involved in aging. Systematically analyzing individual senescence genes and developing functional reference notes will aid in understanding the potential mechanisms underlying aging and identify therapeutic targets for both anti-aging interventions and age-related illnesses.
Topics: Humans; Sirtuins; AMP-Activated Protein Kinases; Cellular Senescence; Aging; Energy Metabolism
PubMed: 37919064
DOI: 10.31083/j.fbl2810250