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Frontiers in Immunology 2023Trauma is a major cause of death worldwide. The post-traumatic immune response culminates in the release of pro-inflammatory mediators, translating in the infiltration...
Trauma is a major cause of death worldwide. The post-traumatic immune response culminates in the release of pro-inflammatory mediators, translating in the infiltration of neutrophils (PMNs) at injury sites. The extent of this inflammation is determined by multiple factors, such as PMN adhesion to the endothelium, transendothelial migration, endothelial barrier integrity as well as PMN swarming, mass infiltration and activation. This process is initiated by secondary lipid mediators, such as leukotriene B (LTB). We here provide evidence that Protein kinase D1 (PRKD1) in endothelial cells is implicated in all these processes. Endothelial PRKD1 is activated by pro-inflammatory stimuli and amplifies PMN-mediated inflammation by upregulation of cytokine and chemokines as well as adhesion molecules, such as ICAM-1, VCAM-1 and E-selectin. This induces enhanced PMN adhesion and trans-migration. PRKD1 activation also destabilizes endothelial VE-cadherin adhesion complexes and thus the endothelial barrier, fostering PMN infiltration. We even describe a yet unrecognized PRKD1-dependant mechanism to induce biosynthesis of the PMN-swarming mediator LTB directed intercellular communication through small extracellular vesicles (sEVs) and enhanced CXCL8 secretion from activated endothelial cells. These endothelial sEVs transfer the LTB biosynthesis enzyme LTA hydrolase (LTAH) to prime PMNs, while initiating biosynthesis also requires additional signals, like CXCL8. We further demonstrate the respective LTAH-positive sEVs in the serum of polytrauma patients, peaking 12 h post injury. Therefore, PRKD1 is a key regulator in the coordinated communication of the endothelium with PMNs and a vital signaling node during post-traumatic inflammation.
Topics: Humans; Cell Adhesion; Endothelial Cells; Endothelium, Vascular; Inflammation; Protein Kinases; Animals; Wounds and Injuries
PubMed: 36936923
DOI: 10.3389/fimmu.2023.1093022 -
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 -
Molecules (Basel, Switzerland) Apr 2023Protein phosphorylation is a ubiquitous post-translational modification controlled by the opposing activities of protein kinases and phosphatases, which regulate diverse... (Review)
Review
Protein phosphorylation is a ubiquitous post-translational modification controlled by the opposing activities of protein kinases and phosphatases, which regulate diverse biological processes in all kingdoms of life. One of the key challenges to a complete understanding of phosphoregulatory networks is the unambiguous identification of kinase and phosphatase substrates. Liquid chromatography-coupled mass spectrometry (LC-MS/MS) and associated phosphoproteomic tools enable global surveys of phosphoproteome changes in response to signaling events or perturbation of phosphoregulatory network components. Despite the power of LC-MS/MS, it is still challenging to directly link kinases and phosphatases to specific substrate phosphorylation sites in many experiments. Here, we survey common LC-MS/MS-based phosphoproteomic workflows for identifying protein kinase and phosphatase substrates, noting key advantages and limitations of each. We conclude by discussing the value of inducible degradation technologies coupled with phosphoproteomics as a new approach that overcomes some limitations of current methods for substrate identification of kinases, phosphatases, and other regulatory enzymes.
Topics: Phosphoric Monoester Hydrolases; Chromatography, Liquid; Tandem Mass Spectrometry; Phosphorylation; Protein Kinases; Phosphoproteins
PubMed: 37175085
DOI: 10.3390/molecules28093675 -
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 -
Plant Signaling & Behavior Dec 2023Hypoxia triggers reactive oxygen species (ROS)-induced elevation in cytoplasmic calcium (Ca) in the plant cells. Calcium-dependent protein kinase 12 (CPK12) acts as a...
Hypoxia triggers reactive oxygen species (ROS)-induced elevation in cytoplasmic calcium (Ca) in the plant cells. Calcium-dependent protein kinase 12 (CPK12) acts as a sensor to recognize the Ca signature and is activated by autophosphorylation. Then, the CPK12 moves into the nucleus with the help of phosphatidic acid (PA) and phosphorylates ERF-VII family proteins that activate hypoxia signaling and response. The study provides a novel mechanism of hypoxia signaling in plants. Moreover, the mechanism of hypoxia-specific Ca signature generation remains elusive.
Topics: Protein Kinases; Hypoxia; Cell Hypoxia; Phosphorylation; Calcium; Reactive Oxygen Species
PubMed: 37875477
DOI: 10.1080/15592324.2023.2273593 -
Cold Spring Harbor Perspectives in... Jul 2019Protein synthesis, including the translation of specific messenger RNAs (mRNAs), is regulated by extracellular stimuli such as hormones and by the levels of certain... (Review)
Review
Protein synthesis, including the translation of specific messenger RNAs (mRNAs), is regulated by extracellular stimuli such as hormones and by the levels of certain nutrients within cells. This control involves several well-understood signaling pathways and protein kinases, which regulate the phosphorylation of proteins that control the translational machinery. These pathways include the mechanistic target of rapamycin complex 1 (mTORC1), its downstream effectors, and the mitogen-activated protein (MAP) kinase (extracellular ligand-regulated kinase [ERK]) signaling pathway. This review describes the regulatory mechanisms that control translation initiation and elongation factors, in particular the effects of phosphorylation on their interactions or activities. It also discusses current knowledge concerning the impact of these control systems on the translation of specific mRNAs or subsets of mRNAs, both in physiological processes and in diseases such as cancer.
Topics: Gene Expression Regulation; Mechanistic Target of Rapamycin Complex 1; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Protein Biosynthesis; Signal Transduction
PubMed: 29959191
DOI: 10.1101/cshperspect.a033050 -
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 -
The Journal of Biological Chemistry Oct 2019Protein kinase signaling networks stringently regulate cellular processes, such as proliferation, motility, and cell survival. These networks are also central to the... (Review)
Review
Protein kinase signaling networks stringently regulate cellular processes, such as proliferation, motility, and cell survival. These networks are also central to the evolution and progression of cancer. Accordingly, genetically encoded fluorescent biosensors capable of directly illuminating the spatiotemporal dynamics of kinase signaling in live cells are being increasingly used to investigate kinase signaling in cancer cells and tumor tissue sections. These biosensors enable visualization of biological processes and events directly , preserving the native biological context and providing detailed insight into their localization and dynamics in cells. Herein, we first review common design strategies for kinase activity biosensors, including signaling targets, biosensor components, and fluorescent proteins involved. Subsequently, we discuss applications of biosensors to study the biology and management of cancer. These versatile molecular tools have been deployed to study oncogenic kinase signaling in living cells and image kinase activities in tumors or to decipher the mechanisms of anticancer drugs. We anticipate that the diversity and precision of genetically encoded biosensors will expand their use to further unravel the dysregulation of kinase signaling in cancer and the modes of actions of cancer-targeting drugs.
Topics: Biosensing Techniques; Fluorescent Dyes; Green Fluorescent Proteins; Humans; Neoplasms; Phosphorylation; Phosphotransferases; Protein Kinases; Signal Transduction
PubMed: 31434714
DOI: 10.1074/jbc.REV119.006177 -
Proceedings of the National Academy of... Nov 2022Topological analysis of protein residue networks (PRNs) is a common method that can help to understand the roles of individual residues. Here, we used protein kinase A...
Topological analysis of protein residue networks (PRNs) is a common method that can help to understand the roles of individual residues. Here, we used protein kinase A as a study object and asked what already known functionally important residues can be detected by network analysis. Along several traditional approaches to weight edges in PRNs we used local spatial pattern (LSP) alignment that assigns high weights to edges only if CαCβ vectors for the corresponding residues retain their mutual positions and orientation. Our results show that even short molecular dynamic simulations of 10 to 20 ns can give convergent values for betweenness and degree centralities calculated from the LSP-based PRNs. Using these centralities, we were able to clearly distinguish a group of residues that are highly conserved in protein kinases and play important functional and regulatory roles. In comparison, traditional methods based on cross-correlation and linear mutual information were much less efficient for this particular task. These results call for reevaluation of the current methods to generate PRNs.
Topics: Cyclic AMP-Dependent Protein Kinases; Molecular Dynamics Simulation
PubMed: 36375071
DOI: 10.1073/pnas.2215420119 -
Genes Oct 2021Cell death is the ultimate form of cellular dysfunction, and is induced by a wide range of stresses including genotoxic stresses. During genotoxic stress, two opposite... (Review)
Review
Cell death is the ultimate form of cellular dysfunction, and is induced by a wide range of stresses including genotoxic stresses. During genotoxic stress, two opposite cellular reactions, cellular protection through DNA repair and elimination of damaged cells by the induction of cell death, can occur in both separate and simultaneous manners. ATM (ataxia telangiectasia mutated) kinase (hereafter referred to as ATM) is a protein kinase that plays central roles in the induction of cell death during genotoxic stresses. It has long been considered that ATM mediates DNA damage-induced cell death through inducing apoptosis. However, recent research progress in cell death modality is now revealing ATM-dependent cell death pathways that consist of not only apoptosis but also necroptosis, ferroptosis, and dysfunction of autophagy, a cellular survival mechanism. In this short review, we intend to provide a brief outline of cell death mechanisms in which ATM is involved, with emphasis on pathways other than apoptosis.
Topics: Ataxia Telangiectasia Mutated Proteins; Autophagy; Cell Death; DNA Damage; DNA Repair; Humans; Protein Kinases; Signal Transduction
PubMed: 34680975
DOI: 10.3390/genes12101581