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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 -
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 -
Trends in Biochemical Sciences Nov 2016Eukaryotic protein kinases (EPKs) control most biological processes and play central roles in many human diseases. To become catalytically active, EPKs undergo... (Review)
Review
Eukaryotic protein kinases (EPKs) control most biological processes and play central roles in many human diseases. To become catalytically active, EPKs undergo conversion from an inactive to an active conformation, an event that depends upon phosphorylation of their activation loop. Intriguingly, EPKs can use their own catalytic activity to achieve this critical phosphorylation. In other words, paradoxically, EPKs catalyze autophosphorylation when supposedly in their inactive state. This indicates the existence of another important conformation that specifically permits autophosphorylation at the activation loop, which in turn imposes adoption of the active conformation. This can be considered a prone-to-autophosphorylate conformation. Recent findings suggest that in prone-to-autophosphorylate conformations catalytic motifs are aligned allosterically, by dimerization or by regulators, and support autophosphorylation in cis or trans.
Topics: Allosteric Regulation; Allosteric Site; Amino Acid Motifs; Biocatalysis; Catalytic Domain; Gene Expression; Humans; Phosphorylation; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Kinases; Protein Multimerization; Proteome
PubMed: 27594179
DOI: 10.1016/j.tibs.2016.08.006 -
Chemical Society Reviews Apr 2018Protein kinases are involved in the regulation of many cellular processes including cell differentiation, survival, migration, axon guidance and neuronal plasticity. A... (Review)
Review
Protein kinases are involved in the regulation of many cellular processes including cell differentiation, survival, migration, axon guidance and neuronal plasticity. A growing set of optogenetic tools, termed opto-kinases, allows activation and inhibition of different protein kinases with light. The optogenetic regulation enables fast, reversible and non-invasive manipulation of protein kinase activities, complementing traditional methods, such as treatment with growth factors, protein kinase inhibitors or chemical dimerizers. In this review, we summarize the properties of the existing optogenetic tools for controlling tyrosine kinases and serine-threonine kinases. We discuss how the opto-kinases can be applied for studies of spatial and temporal aspects of protein kinase signaling in cells and organisms. We compare approaches for chemical and optogenetic regulation of protein kinase activity and present guidelines for selection of opto-kinases and equipment to control them with light. We also describe strategies to engineer novel opto-kinases on the basis of various photoreceptors.
Topics: Animals; Humans; Optogenetics; Protein Kinases; Signal Transduction
PubMed: 29498733
DOI: 10.1039/c7cs00404d -
Expert Review of Anticancer Therapy Dec 2018Protein kinases are involved in various cellular functions. About 2% of the human genome encodes for protein kinases. Dysregulation of protein kinases is implicated in... (Review)
Review
Protein kinases are involved in various cellular functions. About 2% of the human genome encodes for protein kinases. Dysregulation of protein kinases is implicated in various processes of carcinogenesis. The advent of protein kinase inhibitors in cancer therapy has led to a paradigm shift in cancer therapy. Several protein kinase inhibitors have been approved by FDA in the last few decades. Areas covered: This article provides a review of the FDA approved protein kinase inhibitors as of December 2017 for the well-known oncogenic protein kinases. A list of FDA approved protein kinase inhibitors and their FDA approved clinical indications were cataloged. The role of the respective oncogenic protein kinases in carcinogenesis and cancer progression and the relevant landmark clinical trials of respective protein kinase inhibitors leading up to the FDA approval were PubMed searched and discussed. Expert commentary: Further understanding of the molecular origin of various cancers would help identify new targets. Use of biomarker profiling might select the patient population that would benefit better from kinase inhibitors. Clinical trials should be designed to identify the appropriate sequence of the available kinase inhibitors. It would prove to be useful to test these drugs in the adjuvant setting.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Disease Progression; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Kinases
PubMed: 30259761
DOI: 10.1080/14737140.2018.1527688 -
Genes Jun 2023Tremendous amount of financial resources and manpower have been invested to understand the function of numerous genes that are deregulated during the carcinogenesis... (Review)
Review
Tremendous amount of financial resources and manpower have been invested to understand the function of numerous genes that are deregulated during the carcinogenesis process, which can be targeted for anticancer therapeutic interventions. () is one of the genes that have shown potential as biomarkers for cancer treatment. It is a member of the kinase family, which also includes Death-associated protein kinase 2 (DAPK-2), Death-associated protein kinase 3 (DAPK-3), Death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK-1) and Death-associated protein kinase-related apoptosis-inducing kinase 2 (DRAK-2). is a tumour-suppressor gene that is hypermethylated in most human cancers. Additionally, DAPK-1 regulates a number of cellular processes, including apoptosis, autophagy and the cell cycle. The molecular basis by which DAPK-1 induces these cell homeostasis-related processes for cancer prevention is less understood; hence, they need to be investigated. The purpose of this review is to discuss the current understanding of the mechanisms of DAPK-1 in cell homeostasis-related processes, especially apoptosis, autophagy and the cell cycle. It also explores how the expression of DAPK-1 affects carcinogenesis. Since deregulation of DAPK-1 is implicated in the pathogenesis of cancer, altering DAPK-1 expression or activity may be a promising therapeutic strategy against cancer.
Topics: Humans; Death-Associated Protein Kinases; Calcium-Calmodulin-Dependent Protein Kinases; Apoptosis Regulatory Proteins; Apoptosis; Neoplasms; Carcinogenesis
PubMed: 37372454
DOI: 10.3390/genes14061274 -
Oncogene Mar 2018Protein kinase D2 (PKD2) is a serine/threonine kinase that belongs to the PKD family of calcium-calmodulin kinases, which comprises three isoforms: PKD1, PKD2, and PKD3.... (Review)
Review
Protein kinase D2 (PKD2) is a serine/threonine kinase that belongs to the PKD family of calcium-calmodulin kinases, which comprises three isoforms: PKD1, PKD2, and PKD3. PKD2 is activated by many stimuli including growth factors, phorbol esters, and G-protein-coupled receptor agonists. PKD2 participation to uncontrolled growth, survival, neovascularization, metastasis, and invasion has been documented in various tumor types including pancreatic, colorectal, gastric, hepatic, lung, prostate, and breast cancer, as well as glioma multiforme and leukemia. This review discusses the versatile functions of PKD2 from the perspective of cancer hallmarks as described by Hanahan and Weinberg. The PKD2 status, signaling pathways affected in different tumor types and the molecular mechanisms that lead to tumorigenesis and tumor progression are presented. The latest developments of small-molecule inhibitors selective for PKD/PKD2, as well as the need for further chemotherapies that prevent, slow down, or eliminate tumors are also discussed in this review.
Topics: Animals; Cell Proliferation; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Protein Kinase D2; Protein Kinases; Signal Transduction
PubMed: 29259300
DOI: 10.1038/s41388-017-0052-8 -
Experimental & Molecular Medicine Jun 2021Necroptosis is a form of programmed necrosis that is mediated by various cytokines and pattern recognition receptors (PRRs). Cells dying by necroptosis show necrotic... (Review)
Review
Necroptosis is a form of programmed necrosis that is mediated by various cytokines and pattern recognition receptors (PRRs). Cells dying by necroptosis show necrotic phenotypes, including swelling and membrane rupture, and release damage-associated molecular patterns (DAMPs), inflammatory cytokines, and chemokines, thereby mediating extreme inflammatory responses. Studies on gene knockout or necroptosis-specific inhibitor treatment in animal models have provided extensive evidence regarding the important roles of necroptosis in inflammatory diseases. The necroptosis signaling pathway is primarily modulated by activation of receptor-interacting protein kinase 3 (RIPK3), which phosphorylates mixed-lineage kinase domain-like protein (MLKL), mediating MLKL oligomerization. In the necroptosis process, these proteins are fine-tuned by posttranslational regulation via phosphorylation, ubiquitination, glycosylation, and protein-protein interactions. Herein, we review recent findings on the molecular regulatory mechanisms of necroptosis.
Topics: Animals; Apoptosis; Necroptosis; Necrosis; Phosphorylation; Protein Kinases
PubMed: 34075202
DOI: 10.1038/s12276-021-00634-7 -
World Journal of Gastroenterology Aug 2021Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new... (Review)
Review
Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.
Topics: Apoptosis; Humans; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; p38 Mitogen-Activated Protein Kinases
PubMed: 34497429
DOI: 10.3748/wjg.v27.i30.4963 -
Bioorganic & Medicinal Chemistry Jun 2015Many human protein kinases are regulated by the calcium-sensor protein calmodulin, which binds to a short flexible segment C-terminal to the enzyme's catalytic kinase... (Review)
Review
Many human protein kinases are regulated by the calcium-sensor protein calmodulin, which binds to a short flexible segment C-terminal to the enzyme's catalytic kinase domain. Our understanding of the molecular mechanism of kinase activity regulation by calcium/calmodulin has been advanced by the structures of two protein kinases-calmodulin kinase II and death-associated protein kinase 1-bound to calcium/calmodulin. Comparison of these two structures reveals a surprising level of diversity in the overall kinase-calcium/calmodulin arrangement and functional readout of activity, as well as complementary mechanisms of kinase regulation such as phosphorylation.
Topics: Amino Acid Sequence; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Death-Associated Protein Kinases; Humans; Models, Molecular; Molecular Sequence Data; Protein Conformation; Sequence Alignment
PubMed: 25963826
DOI: 10.1016/j.bmc.2015.04.051