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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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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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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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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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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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PINK1/Parkin mitophagy and neurodegeneration-what do we really know in vivo?
Whitworth, AJ, Pallanck, LJ
Current opinion in genetics & development. 2017;:47-53
Abstract
Mitochondria are essential organelles that provide cellular energy and buffer cytoplasmic calcium. At the same time they produce damaging reactive oxygen species and sequester pro-apoptotic factors. Hence, eukaryotes have evolved exquisite homeostatic processes that maintain mitochondrial integrity, or ultimately remove damaged organelles. This subject has garnered intense interest recently following the discovery that two Parkinson's disease genes, PINK1 and parkin, regulate mitochondrial degradation (mitophagy). The molecular details of PINK1/Parkin-induced mitophagy are emerging but much of our insight derives from work using cultured cells and potent mitochondrial toxins, raising questions about the physiological significance of these findings. Here we review the evidence supporting PINK1/Parkin mitophagy in vivo and its causative role in neurodegeneration, and outline outstanding questions for future investigations.
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Coenzyme Q10 supplementation therapy for 2 children with proteinuria renal disease and ADCK4 mutation: Case reports and literature review.
Feng, C, Wang, Q, Wang, J, Liu, F, Shen, H, Fu, H, Mao, J
Medicine. 2017;(47):e8880
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Abstract
RATIONALE Mitochondrial nephropathy has a poor prognosis and often progresses to the end-stage renal disease. Renal pathology often is focal segmental glomerulosclerosis (FSGS) and does not respond to steroid therapy or immunosuppressive therapy. Some patients are benefited from the therapy of coenzyme Q10, which affect the synthesis pathway of coenzyme Q10. PATIENT CONCERNS Herein, we report 2 cases of children with proteinuria renal disease with ADCK4 mutation. DIAGNOSES Proteinuria renal disease with ADCK4 mutation. INTERVENTIONS Compound heterozygous mutation in ADCK4 gene were detected with next-generation sequencing and confirmed by Sanger sequencing. Both of the patients were given coenzyme Q10 supplementation therapy. OUTCOMES The first patient showed a decreased proteinuria after coenzyme Q10 supplementation therapy, while the other was not improved. LESSONS Based on the cases we reported and from the literature, recognition of ADCK4 mutation through early and accurate genetic screening could be helpful in avoiding unnecessary toxicities and in preventing complications arising in mitochondrial nephropathy.
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L-type lectin receptor kinases: New forces in plant immunity.
Wang, Y, Bouwmeester, K
PLoS pathogens. 2017;(8):e1006433
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The eukaryotic protein kinase superfamily of the necrotrophic fungal plant pathogen, Sclerotinia sclerotiorum.
Hegedus, DD, Gerbrandt, K, Coutu, C
Molecular plant pathology. 2016;(4):634-47
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Abstract
Protein kinases have been implicated in the regulation of many processes that guide pathogen development throughout the course of infection. A survey of the Sclerotinia sclerotiorum genome for genes encoding proteins containing the highly conserved eukaryotic protein kinase (ePK) domain, the largest protein kinase superfamily, revealed 92 S. sclerotiorum ePKs. This review examines the composition of the S. sclerotiorum ePKs based on conserved motifs within the ePK domain family, and relates this to orthologues found in other filamentous fungi and yeasts. The ePKs are also discussed in terms of their proposed role(s) in aspects of host pathogenesis, including the coordination of mycelial growth/development and deployment of pathogenicity determinants in response to environmental stimuli, nutrients and stress.
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A brief history of the TDIF-PXY signalling module: balancing meristem identity and differentiation during vascular development.
Etchells, JP, Smit, ME, Gaudinier, A, Williams, CJ, Brady, SM
The New phytologist. 2016;(2):474-84
Abstract
474 I. 474 II. 475 III. 475 IV. 477 V. 477 VI. 477 VII. 479 VIII. 481 482 References 482 SUMMARY A significant proportion of terrestrial biomass is constituted of xylem cells that make up woody plant tissue. Xylem is required for water transport, and is present in the vascular tissue with a second conductive tissue, phloem, required primarily for nutrient transport. Both xylem and phloem are derived from cell divisions in vascular meristems known as the cambium and procambium. One major component that influences several aspects of plant vascular development, including cell division in the vascular meristem, vascular organization and differentiation of vascular cell types, is a signalling module characterized by a peptide ligand called TRACHEARY ELEMENT DIFFERENTIATION INHIBITORY FACTOR (TDIF) and its cognate receptor, PHLOEM INTERCALATED WITH XYLEM (PXY). In this review, we explore the literature that describes signalling components, phytohormones and transcription factors that interact with these two central factors, to control the varying outputs required in vascular tissues for normal organization and elaboration of plant vascular tissue.