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1.
Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview.
Lindberg, MF, Meijer, L
International journal of molecular sciences. 2021;(11)
Abstract
Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer's disease and related diseases, tauopathies, dementia, Pick's disease, Parkinson's disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.
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With no lysine kinases: the key regulatory networks and phytohormone cross talk in plant growth, development and stress response.
Saddhe, AA, Karle, SB, Aftab, T, Kumar, K
Plant cell reports. 2021;(11):2097-2109
Abstract
With No Lysine kinases (WNKs) are a distinct family of Serine/Threonine protein kinase with unique arrangement of catalytic residues in kinase domain. In WNK, an essential catalytic lysine requisite for attaching ATP and phosphorylation reaction is located in subdomain I, instead of subdomain II, which is essentially a typical feature of other Ser/Thr kinases. WNKs are identified in diverse organisms including multicellular and unicellular organisms. Mammalian WNKs are well characterized at structural and functional level, while plant WNKs are not explored much except few recent studies. Plant WNKs role in various physiological processes viz. ion maintenance, osmotic stress, pH homeostasis, circadian rhythms, regulation of flowering time, proliferation and organ development, and abiotic stresses are known, but the mechanisms involved are unclear. Plant WNKs are known to be involved in enhanced drought and salt stress response via ABA-signaling pathway, but the complete signaling cascade is yet to be elucidated. The current review will discuss the interplay between WNKs and growth regulators and their cross talks in plant growth and development. We have also highlighted the link between the stress phytohormones and WNK members in regulating abiotic stress responses in plants. The present review will provide an overall known mechanism on the involvement of WNKs in plant growth and development and abiotic stress response and highlight its role/applications in the development of stress-tolerant plants.
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Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke.
Josiah, SS, Meor Azlan, NF, Zhang, J
International journal of molecular sciences. 2021;(3)
Abstract
Stroke is one of the major culprits responsible for morbidity and mortality worldwide, and the currently available pharmacological strategies to combat this global disease are scanty. Cation-chloride cotransporters (CCCs) are expressed in several tissues (including neurons) and extensively contribute to the maintenance of numerous physiological functions including chloride homeostasis. Previous studies have implicated two CCCs, the Na+-K+-Cl- and K+-Cl- cotransporters (NKCCs and KCCs) in stroke episodes along with their upstream regulators, the with-no-lysine kinase (WNKs) family and STE20/SPS1-related proline/alanine rich kinase (SPAK) or oxidative stress response kinase (OSR1) via a signaling pathway. As the WNK-SPAK/OSR1 pathway reciprocally regulates NKCC and KCC, a growing body of evidence implicates over-activation and altered expression of NKCC1 in stroke pathology whilst stimulation of KCC3 during and even after a stroke event is neuroprotective. Both inhibition of NKCC1 and activation of KCC3 exert neuroprotection through reduction in intracellular chloride levels and thus could be a novel therapeutic strategy. Hence, this review summarizes the current understanding of functional regulations of the CCCs implicated in stroke with particular focus on NKCC1, KCC3, and WNK-SPAK/OSR1 signaling and discusses the current and potential pharmacological treatments for stroke.
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4.
The SnRK2 family in pepper (Capsicum annuum L.): genome-wide identification and expression analyses during fruit development and under abiotic stress.
Wu, Z, Cheng, J, Hu, F, Qin, C, Xu, X, Hu, K
Genes & genomics. 2020;(10):1117-1130
Abstract
Plant-specific SnRK2 (sucrose nonfermenting-1-related protein kinase 2) genes play crucial roles in the coordination of plant growth and development and responses to stress. However, comprehensive studies have not been performed for this gene family in pepper (Capsicum annuum), a very important Solanaceous vegetable worldwide. To fully understand the status of SnRK2s in chili pepper, a total of 9 putative SnRK2 genes (named CaSnRK2.1-2.9) were identified in pepper in the present study. These genes were located on 7 different chromosomes and classified into three subfamilies based on the phylogenetic tree. Their conserved motif compositions and exon-intron structures were systematically analyzed, and the results strongly supported the classification. Furthermore, a total of 81 putative cis-elements were found in the promoter regions, and the cis-elements related to hormone and stress signaling were abundant. Finally, the CaSnRK2 gene expression profiles among different tissues, especially developing fruit tissue, and under various abiotic stresses were investigated to identify tissue-specific or stress-responsive candidates. This study was the first to comprehensively investigate the SnRK2 family in pepper, and the results provide important clues for further functional analyses of fruit development and abiotic stress responses.
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5.
Role of Raf-like kinases in SnRK2 activation and osmotic stress response in plants.
Fàbregas, N, Yoshida, T, Fernie, AR
Nature communications. 2020;(1):6184
Abstract
Environmental drought and high salinity impose osmotic stress, which inhibits plant growth and yield. Thus, understanding how plants respond to osmotic stress is critical to improve crop productivity. Plants have multiple signalling pathways in response to osmotic stress in which the phytohormone abscisic acid (ABA) plays important roles. However, since little is known concerning key early components, the global osmotic stress-signalling network remains to be elucidated. Here, we review recent advances in the identification of osmotic-stress activated Raf-like protein kinases as regulators of ABA-dependent and -independent signalling pathways and discuss the plant stress-responsive kinase network from an evolutionary perspective.
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6.
Cataloguing the dead: breathing new life into pseudokinase research.
Shrestha, S, Byrne, DP, Harris, JA, Kannan, N, Eyers, PA
The FEBS journal. 2020;(19):4150-4169
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Abstract
Pseudoenzymes are present within many, but not all, known enzyme families and lack one or more conserved canonical amino acids that help define their catalytically active counterparts. Recent findings in the pseudokinase field confirm that evolutionary repurposing of the structurally defined bilobal protein kinase fold permits distinct biological functions to emerge, many of which rely on conformational switching, as opposed to canonical catalysis. In this analysis, we evaluate progress in evaluating several members of the 'dark' pseudokinome that are pertinent to help drive this expanding field. Initially, we discuss how adaptions in erythropoietin-producing hepatocellular carcinoma (Eph) receptor tyrosine kinase domains resulted in two vertebrate pseudokinases, EphA10 and EphB6, in which co-evolving sequences generate new motifs that are likely to be important for both nucleotide binding and catalysis-independent signalling. Secondly, we discuss how conformationally flexible Tribbles pseudokinases, which have radiated in the complex vertebrates, control fundamental aspects of cell signalling that may be targetable with covalent small molecules. Finally, we show how species-level adaptions in the duplicated canonical kinase protein serine kinase histone (PSKH)1 sequence have led to the appearance of the pseudokinase PSKH2, whose physiological role remains mysterious. In conclusion, we show how the patterns we discover are selectively conserved within specific pseudokinases, and that when they are modelled alongside closely related canonical kinases, many are found to be located in functionally important regions of the conserved kinase fold. Interrogation of these patterns will be useful for future evaluation of these, and other, members of the unstudied human kinome.
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7.
The interplay of renal potassium and sodium handling in blood pressure regulation: critical role of the WNK-SPAK-NCC pathway.
Wu, A, Wolley, M, Stowasser, M
Journal of human hypertension. 2019;(7):508-523
Abstract
Renal salt handling has a profound effect on body fluid and blood pressure (BP) maintenance as exemplified by the use of diuretic medications to treat states of volume expansion or hypertension. It has recently been proposed that a low potassium (K+) intake turns on a "renal K+ switch" which increases sodium (Na+) and chloride (Cl-) reabsorption, causing salt-retention, and in susceptible individuals, this causes hypertension. A signaling network, involving with-no-lysine (WNK) kinases, underpins the switch activity to coordinate aldosterone's two essential actions (K+ secretion and Na+ retention). A dysfunctional WNK kinase network drives excessive and inappropriate Na+, Cl- and urinary K+ retention in familial hyperkalemic hypertension (FHHt, also known as Gordon's syndrome). Mutations in genes encoding WNK1 and WNK4 or components of an ubiquitin ligase complex, cullin3, and kelch-like family member 3 (KLHL3), cause FHHt by upregulating the thiazide-sensitive sodium chloride cotransporter (NCC). Inhibition of NCC with thiazide diuretics corrects hypertension and hyperkalaemia in FHHt. These observations highlight the critical role of the NCC in the regulation of Na+ and K+ balance and of BP. Here we discuss the physiology of Na+ and K+ handling in the distal renal tubule with respect to BP regulation, with a focus on recent discoveries in the WNK- Ste20-related proline-alanine-rich kinase (SPAK)-NCC pathway.
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Nutrient Sensing and Redox Balance: GCN2 as a New Integrator in Aging.
Falcón, P, Escandón, M, Brito, Á, Matus, S
Oxidative medicine and cellular longevity. 2019;:5730532
Abstract
Aging is a complex process in which the accumulation of molecular, cellular, and organism dysfunction increases the probability of death. Several pieces of evidence have revealed a contribution of stress responses in aging and in aging-related diseases, in particular, the key role of signaling pathways associated to nutritional stress. Here, we review the possible interplay between amino acid sensing and redox balance maintenance mediated by the nutritional sensor general control nonderepressive 2 (GCN2). We discuss this new dimension of nutritional stress sensing consequences, standing out GCN2 as a central coordinator of key cellular processes that assure healthy homeostasis in the cell, raising GCN2 as a novel interesting target, that when activated, could imply pleiotropic benefits, particularly GCN2 intervention and its new unexplored therapeutic role as a player in the aging process.
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The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1.
Xu, X, Chen, Y, Fu, Q, Ni, D, Zhang, J, Li, X, Lu, S
Journal of enzyme inhibition and medicinal chemistry. 2019;(1):361-374
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Abstract
Phosphoinositide-dependent protein kinase-1 (PDK1) is an important protein in mediating the PI3K-AKT pathway and is thus identified as a promising target. The catalytic activity of PDK1 is tightly regulated by allosteric modulators, which bind to the PDK1 Interacting Fragment (PIF) pocket of the kinase domain that is topographically distinct from the orthosteric, ATP binding site. Allosteric modulators by attaching to the less conserved PIF-pocket have remarkable advantages such as higher selectivity, less side effect, and lower toxicity. Targeting allosteric PIF-pocket of PDK1 has become the focus of recent attention. In this review, we summarise the current advances in the structure-based discovery of PDK1 allosteric modulators. We will first present the three-dimensional structure of PDK1 and illustrate the allosteric regulatory mechanism of PDK1 through the modulation of the PIF-pocket. Then, the recent advances of PDK1 allosteric modulators targeting the PIF-pocket will be recapitulated detailly according to the structural similarity of allosteric modulators.
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10.
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.