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1.
Ca2+-CBL-CIPK: a modulator system for efficient nutrient acquisition.
Verma, P, Sanyal, SK, Pandey, GK
Plant cell reports. 2021;(11):2111-2122
Abstract
Calcium (Ca2+) is a universal second messenger essential for the growth and development of plants in normal and stress situations. In plants, the proteins, CBL (calcineurin B-like) and CIPK (CBL-interacting protein kinase), form one of the important Ca2+ decoding complexes to decipher Ca2+ signals elicited by environmental challenges. Multiple interactors distinguish CBL and CIPK protein family members to form a signaling network for regulated perception and transduction of environmental signals, e.g., signals generated under nutrient stress conditions. Conservation of equilibrium in response to varying soil nutrient status is an important aspect for plant vigor and yield. Signaling processes have been reported to observe nutrient fluctuations as a signal responsible for regulated nutrient transport adaptation. Recent studies have identified downstream targets of CBL-CIPK modules as ion channels or transporters and their association in signaling nutrient disposal including potassium, nitrate, ammonium, magnesium, zinc, boron, and iron. Ca2+-CBL-CIPK pathway modulates ion transporters/channels and hence maintains a homeostasis of several important plant nutrients in the cytosol and sub-cellular compartments. In this article, we summarize recent literature to discuss the role of the Ca2+-CBL-CIPK pathway in cellular osmoregulation and homeostasis on exposure to nutrient excess or deprived soils. This further establishes a link between taking up the nutrient in the roots and its distribution and homeostasis during the generation of signal for the development and survival of plants.
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2.
Dysregulation of Wnt/β-catenin signaling by protein kinases in hepatocellular carcinoma and its therapeutic application.
Li, Q, Sun, M, Wang, M, Feng, M, Yang, F, Li, L, Zhao, J, Chang, C, Dong, H, Xie, T, et al
Cancer science. 2021;(5):1695-1706
Abstract
Wnt/β-catenin signaling is indispensable for many biological processes, including embryonic development, cell cycle, inflammation, and carcinogenesis. Aberrant activation of the Wnt/β-catenin signaling can promote tumorigenicity and enhance metastatic potential in hepatocellular carcinoma (HCC). Targeting this pathway is a new opportunity for precise medicine for HCC. However, inhibiting Wnt/β-catenin signaling alone is unlikely to significantly improve HCC patient outcome due to the lack of specific inhibitors and the complexity of this pathway. Combination with other therapies will be an important next step in improving the efficacy of Wnt/β-catenin signaling inhibitors. Protein kinases play a key and evolutionarily conserved role in the Wnt/β-catenin signaling and have become one of the most important drug targets in cancer. Targeting Wnt/β-catenin signaling and its regulatory kinase together will be a promising HCC management strategy. In this review, we summarize the kinases that modulate the Wnt/β-catenin signaling in HCC and briefly discuss their molecular mechanisms. Furthermore, we list some small molecules that target the kinases and may inhibit Wnt/β-catenin signaling, to offer new perspectives for preclinical and clinical HCC studies.
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3.
Potential for Protein Kinase Pharmacological Regulation in Flaviviridae Infections.
Blázquez, AB, Saiz, JC
International journal of molecular sciences. 2020;(24)
Abstract
Protein kinases (PKs) are enzymes that catalyze the transfer of the terminal phosphate group from ATP to a protein acceptor, mainly to serine, threonine, and tyrosine residues. PK catalyzed phosphorylation is critical to the regulation of cellular signaling pathways that affect crucial cell processes, such as growth, differentiation, and metabolism. PKs represent attractive targets for drugs against a wide spectrum of diseases, including viral infections. Two different approaches are being applied in the search for antivirals: compounds directed against viral targets (direct-acting antivirals, DAAs), or against cellular components essential for the viral life cycle (host-directed antivirals, HDAs). One of the main drawbacks of DAAs is the rapid emergence of drug-resistant viruses. In contrast, HDAs present a higher barrier to resistance development. This work reviews the use of chemicals that target cellular PKs as HDAs against virus of the Flaviviridae family (Flavivirus and Hepacivirus), thus being potentially valuable therapeutic targets in the control of these pathogens.
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4.
Early-onset COQ8B (ADCK4) glomerulopathy in a child with isolated proteinuria: a case report and literature review.
Zhai, SB, Zhang, L, Sun, BC, Zhang, Y, Ma, QS
BMC nephrology. 2020;(1):406
Abstract
BACKGROUND Herein, a 3-year-old boy presented with hidden-onset isolated proteinuria was reported. The disease was induced by COQ8B (previously termed ADCK4) compound heterozygous variants, including c.[271C > T] and c.[737G > A], which were inherited from his father and mother, respectively. CASE PRESENTATION The patient visited our clinic due to non-nephrotic range proteinuria for 3 months, but no obvious abnormality was detected in the vital signs or laboratory test results. Renal histopathology revealed mitochondrial nephropathy, which manifested as mild glomerular abnormalities under light microscope, together with mitochondrial proliferation and hypertrophy and crowded arrangement under electron microscope. As suggested by whole exome sequencing, the patient inherited the COQ8B compound heterozygous variants from both of his parents who showed normal phenotype. After literature review, it was confirmed that one of the variant site (c.[271C > T]) had not been reported among the East Asian populations so far. CONCLUSIONS Steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis are the most common phenotypes and renal histopathological manifestations of COQ8B variant. Nonetheless, our case shows that such variant may have hidden and mild clinical manifestations at the early onset. Therefore, early diagnosis will help to identify children at the early disease stage who have opportunity to benefit from oral coenzyme Q10 supplementation.
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5.
Carbazole Derivatives as Kinase-Targeting Inhibitors for Cancer Treatment.
Ceramella, J, Iacopetta, D, Barbarossa, A, Caruso, A, Grande, F, Bonomo, MG, Mariconda, A, Longo, P, Carmela, S, Sinicropi, MS
Mini reviews in medicinal chemistry. 2020;(6):444-465
Abstract
Protein Kinases (PKs) are a heterogeneous family of enzymes that modulate several biological pathways, including cell division, cytoskeletal rearrangement, differentiation and apoptosis. In particular, due to their crucial role during human tumorigenesis and cancer progression, PKs are ideal targets for the design and development of effective and low toxic chemotherapeutics and represent the second group of drug targets after G-protein-coupled receptors. Nowadays, several compounds have been claimed to be PKs inhibitors, and some of them, such as imatinib, erlotinib and gefitinib, have already been approved for clinical use, whereas more than 30 others are in various phases of clinical trials. Among them, some natural or synthetic carbazole-based molecules represent promising PKs inhibitors due to their capability to interfere with PK activity by different mechanisms of action including the ability to act as DNA intercalating agents, interfere with the activity of enzymes involved in DNA duplication, such as topoisomerases and telomerases, and inhibit other proteins such as cyclindependent kinases or antagonize estrogen receptors. Thus, carbazoles can be considered a promising this class of compounds to be adopted in targeted therapy of different types of cancer.
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6.
Receptor-Like Kinases Sustain Symbiotic Scrutiny.
Chiu, CH, Paszkowski, U
Plant physiology. 2020;(4):1597-1612
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Abstract
Plant receptor-like kinases (RLKs) control the initiation, development, and maintenance of symbioses with beneficial mycorrhizal fungi and nitrogen-fixing bacteria. Carbohydrate perception activates symbiosis signaling via Lysin-motif RLKs and subsequently the common symbiosis signaling pathway. As the receptors activated are often also immune receptors in multiple species, exactly how carbohydrate identities avoid immune activation and drive symbiotic outcome is still not fully understood. This may involve the coincident detection of additional signaling molecules that provide specificity. Because of the metabolic costs of supporting symbionts, the level of symbiosis development is fine-tuned by a range of local and mobile signals that are activated by various RLKs. Beyond early, precontact symbiotic signaling, signal exchanges ensue throughout infection, nutrient exchange, and turnover of symbiosis. Here, we review the latest understanding of plant symbiosis signaling from the perspective of RLK-mediated pathways.
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7.
The Arabidopsis Calcium-Dependent Protein Kinases (CDPKs) and Their Roles in Plant Growth Regulation and Abiotic Stress Responses.
Shi, S, Li, S, Asim, M, Mao, J, Xu, D, Ullah, Z, Liu, G, Wang, Q, Liu, H
International journal of molecular sciences. 2018;(7)
Abstract
As a ubiquitous secondary messenger in plant signaling systems, calcium ions (Ca2+) play essential roles in plant growth and development. Within the cellular signaling network, the accurate decoding of diverse Ca2+ signal is a fundamental molecular event. Calcium-dependent protein kinases (CDPKs), identified commonly in plants, are a kind of vital regulatory protein deciphering calcium signals triggered by various developmental and environmental stimuli. This review chiefly introduces Ca2+ distribution in plant cells, the classification of Arabidopsis thaliana CDPKs (AtCDPKs), the identification of the Ca2+-AtCDPK signal transduction mechanism and AtCDPKs’ functions involved in plant growth regulation and abiotic stress responses. The review presents a comprehensive overview of AtCDPKs and may contribute to the research of CDPKs in other plants.
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8.
Greatwall kinase at a glance.
Castro, A, Lorca, T
Journal of cell science. 2018;(20)
Abstract
Mitosis is controlled by a subtle balance between kinase and phosphatase activities that involve the master mitotic kinase cyclin-B-Cdk1 and its antagonizing protein phosphatase 2A-B55 (PP2A-B55). Importantly, the Greatwall (Gwl; known as Mastl in mammals, Rim15 in budding yeast and Ppk18 in fission yeast) kinase pathway regulates PP2A-B55 activity by phosphorylating two proteins, cAMP-regulated phosphoprotein 19 (Arpp19) and α-endosulfine (ENSA). This phosphorylation turns these proteins into potent inhibitors of PP2A-B55, thereby promoting a correct timing and progression of mitosis. In this Cell Science at a Glance article and the accompanying poster, we discuss how Gwl is regulated in space and time, and how the Gwl-Arpp19-ENSA-PP2A-B55 pathway plays an essential role in the control of M and S phases from yeast to human. We also summarize how Gwl modulates oncogenic properties of cells and how nutrient deprivation influences Gwl activity.
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9.
PINK1 signaling in mitochondrial homeostasis and in aging (Review).
Kitagishi, Y, Nakano, N, Ogino, M, Ichimura, M, Minami, A, Matsuda, S
International journal of molecular medicine. 2017;(1):3-8
Abstract
Mitochondrial dysfunction is involved in the pathology of Parkinson's disease, an age-associated neurodegenerative disorder. Phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1 (PINK1) is responsible for the most common form of recessive Parkinson's disease. PINK1 is a mitochondrial kinase that is involved in mitrochondrial quality control and promotes cell survival. PINK1 has been shown to protect against neuronal cell death induced by oxidative stress. Accordingly, PINK1 deficiency is associated with mitochondrial dysfunction as well as increased oxidative cellular stress and subsequent neuronal cell death. In addition, several mitochondrial chaperone proteins have been shown to be substrates of the PINK1 kinase. In this review, we discuss recent studies concerning the signaling cascades and molecular mechanisms involved in the process of mitophagy, which is implicated in neurodegeneration and in related aging associated with oxidative stress. Particular attention will be given to the molecular mechanisms proposed to explain the effects of natural compounds and/or food ingredients against oxidative stress. Knowledge of the molecular mechanisms involved in this cellular protection could be critical for developing treatments to prevent and control excessive progression of neurodegenerative disorders.
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10.
Human Protein Kinases and Obesity.
Engin, A
Advances in experimental medicine and biology. 2017;:111-134
Abstract
The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity, and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified by the target amino acid in their substrates. Some protein kinases can phosphorylate both serine/threonine, as well as tyrosine residues. This group of kinases has been known as dual specificity kinases. Unlike the dual specificity kinases, a heterogeneous group of protein phosphatases are known as dual-specificity phosphatases. These phosphatases remove phosphate groups from tyrosine and serine/threonine residues on their substrate. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases. The protein kinase-phosphoproteins interactions play an important role in obesity . In obesity, the pro- and anti-inflammatory effects of adipokines and cytokines through intracellular signaling pathways mainly involve the nuclear factor kappa B (NF-kappaB) and the c-Jun N-terminal kinase (JNK) systems as well as the inhibitor of kappaB-kinase beta (IKK beta). Impairment of insulin signaling in obesity is largely mediated by the activation of the IKKbeta and the JNK. Furthermore, oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2alpha kinase (PERK) and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. Increase in intracellular oxidative stress can promote PKC-beta activation. Activated PKC-beta induces growth factor adapter Shc phosphorylation. Shc-generated peroxides reduce mitochondrial oxygen consumption and enhances triglyceride accumulation. Obesity is fundamentally caused by cellular energy imbalance and dysregulation. Like adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), N-terminal Per-ARNT-Sim (PAS) kinase are nutrient responsive protein kinases and important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular level. Defective responses of AMPK to leptin may contribute to resistance to leptin action on food intake and energy expenditure in obese states.