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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 -
Frontiers in Immunology 2022Upon infection, the herpes viruses create a cellular environment suitable for survival, but innate immunity plays a vital role in cellular resistance to viral infection.... (Review)
Review
Upon infection, the herpes viruses create a cellular environment suitable for survival, but innate immunity plays a vital role in cellular resistance to viral infection. The UL13 protein of herpesviruses is conserved among all herpesviruses and is a serine/threonine protein kinase, which plays a vital role in escaping innate immunity and promoting viral replication. On the one hand, it can target various immune signaling pathways , such as the cGAS-STING pathway and the NF-κB pathway. On the other hand, it phosphorylates regulatory many cellular and viral proteins for promoting the lytic cycle. This paper reviews the research progress of the conserved herpesvirus protein kinase UL13 in immune escape and viral replication to provide a basis for elucidating the pathogenic mechanism of herpesviruses, as well as providing insights into the potential means of immune escape and viral replication of other herpesviruses that have not yet resolved the function of it.
Topics: Protein Kinases; Virus Replication; Simplexvirus; Protein Serine-Threonine Kinases; Viral Proteins
PubMed: 36531988
DOI: 10.3389/fimmu.2022.1088690 -
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 -
International Journal of Molecular... Jun 2023In recent years, three emerging cell deaths, ferroptosis, necroptosis and pyroptosis, have gradually attracted everyone's attention, and they also play an important role... (Review)
Review
In recent years, three emerging cell deaths, ferroptosis, necroptosis and pyroptosis, have gradually attracted everyone's attention, and they also play an important role in the occurrence and development of various diseases. Ferroptosis is an idiographic iron-dependent form regulated cell death with the hallmark of accumulation of the intracellular reactive oxygen species (ROS). Necroptosis is a form of regulated necrotic cell death mediated by the receptor-interacting protein kinase 1(RIPK1) and receptor-interacting protein kinase 3RIPK3. Pyroptosis, also known as cell inflammatory necrosis, is a programmed cell necrosis mediated by Gasdermin D (GSDMD). It is manifested by the continuous swelling of the cells until the cell membrane ruptures, resulting in the release of the cell contents and the activation of a strong inflammatory response. Neurological disorders remain a clinical challenge and patients do not respond well to conventional treatments. Nerve cell death can aggravate the occurrence and development of neurological diseases. This article reviews the specific mechanisms of these three types of cell death and their relationship with neurological diseases and the evidence for the role of the three types of cell death in neurological diseases; understanding these pathways and their mechanisms is helpful for the treatment of neurological diseases.
Topics: Humans; Pyroptosis; Apoptosis; Ferroptosis; Necroptosis; Necrosis; Nervous System Diseases; Protein Kinases
PubMed: 37373274
DOI: 10.3390/ijms241210127 -
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 -
Genes Jun 2020In quiescent cells, primary cilia function as a mechanosensor that converts mechanic signals into chemical activities. This unique organelle plays a critical role in... (Review)
Review
In quiescent cells, primary cilia function as a mechanosensor that converts mechanic signals into chemical activities. This unique organelle plays a critical role in restricting mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is essential for quiescent cells to maintain their quiescence. Multiple mechanisms have been identified that mediate the inhibitory effect of primary cilia on mTORC1 signaling. These mechanisms depend on several tumor suppressor proteins localized within the ciliary compartment, including liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK), polycystin-1, and polycystin-2. Conversely, changes in mTORC1 activity are able to affect ciliogenesis and stability indirectly through autophagy. In this review, we summarize recent advances in our understanding of the reciprocal regulation of mTORC1 and primary cilia.
Topics: AMP-Activated Protein Kinase Kinases; Autophagy; Cilia; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanotransduction, Cellular; Protein Kinases; Protein Serine-Threonine Kinases; Signal Transduction; TRPP Cation Channels
PubMed: 32604881
DOI: 10.3390/genes11060711 -
Trends in Biochemical Sciences Apr 2021Cell cycle checkpoints secure ordered progression from one cell cycle phase to the next. They are important to signal cell stress and DNA lesions and to stop cell cycle... (Review)
Review
Cell cycle checkpoints secure ordered progression from one cell cycle phase to the next. They are important to signal cell stress and DNA lesions and to stop cell cycle progression when severe problems occur. Recent work suggests, however, that the cell cycle control machinery responds in more subtle and sophisticated ways when cells are faced with naturally occurring challenges, such as replication impediments associated with endogenous replication stress. Instead of following a stop and go approach, cells use fine-tuned deceleration and brake release mechanisms under the control of ataxia telangiectasia and Rad3-related protein kinase (ATR) and checkpoint kinase 1 (CHK1) to more flexibly adapt their cell cycle program to changing conditions. We highlight emerging examples of such intrinsic cell cycle checkpoint regulation and discuss their physiological and clinical relevance.
Topics: Ataxia Telangiectasia Mutated Proteins; Cell Cycle; Cell Cycle Checkpoints; Cell Cycle Proteins; DNA Damage; DNA Replication; Phosphorylation; Protein Kinases
PubMed: 33279370
DOI: 10.1016/j.tibs.2020.11.002