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The Plant Cell Jul 2022
Topics: Arabidopsis; Arabidopsis Proteins; Phosphotransferases
PubMed: 35474018
DOI: 10.1093/plcell/koac112 -
Nucleic Acids Research Jan 2021Mutations in kinases are abundant and critical to study signaling pathways and regulatory roles in human disease, especially in cancer. Somatic mutations in kinase genes...
Mutations in kinases are abundant and critical to study signaling pathways and regulatory roles in human disease, especially in cancer. Somatic mutations in kinase genes can affect drug treatment, both sensitivity and resistance, to clinically used kinase inhibitors. Here, we present a newly constructed database, KinaseMD (kinase mutations and drug response), to structurally and functionally annotate kinase mutations. KinaseMD integrates 679 374 somatic mutations, 251 522 network-rewiring events, and 390 460 drug response records curated from various sources for 547 kinases. We uniquely annotate the mutations and kinase inhibitor response in four types of protein substructures (gatekeeper, A-loop, G-loop and αC-helix) that are linked to kinase inhibitor resistance in literature. In addition, we annotate functional mutations that may rewire kinase regulatory network and report four phosphorylation signals (gain, loss, up-regulation and down-regulation). Overall, KinaseMD provides the most updated information on mutations, unique annotations of drug response especially drug resistance and functional sites of kinases. KinaseMD is accessible at https://bioinfo.uth.edu/kmd/, having functions for searching, browsing and downloading data. To our knowledge, there has been no systematic annotation of these structural mutations linking to kinase inhibitor response. In summary, KinaseMD is a centralized database for kinase mutations and drug response.
Topics: Databases, Genetic; Drug Resistance, Neoplasm; Molecular Sequence Annotation; Mutation; Phosphorylation; Phosphotransferases; Protein Kinase Inhibitors; User-Computer Interface
PubMed: 33137204
DOI: 10.1093/nar/gkaa945 -
The Plant Journal : For Cell and... Nov 2020Root nutation indicates the behavior that roots grow in a waving and skewing way due to unequal growth rates on different sides. Although a few developmental and...
Root nutation indicates the behavior that roots grow in a waving and skewing way due to unequal growth rates on different sides. Although a few developmental and environmental factors have been reported, genetic pathways mediating this process are obscure. We report here that the Arabidopsis CrRLK1L family member FERONIA (FER) is critical for root nutation. Functional loss of FER resulted in enhanced root waviness on tilted plates or roots forming anti-clockwise coils on horizontal plates. Suppressing polar auxin transport, either by pharmacological treatment or by introducing mutations at PIN-FORMED2 (PIN2) or AUXIN RESISTANT1 (AUX1), suppressed the asymmetric root growth (ARG) in fer-4, a null mutant of FER, indicating that FER suppression of ARG depends on polar auxin transport. We further showed by pharmacological treatments that dynamic microtubule organization and Ca signaling are both critical for FER-mediated ARG. Results presented here demonstrate a key role of FER in mediating root nutating growth, through PIN2- and AUX1-mediated auxin transport, through dynamic microtubule organization, and through Ca signaling.
Topics: Arabidopsis; Arabidopsis Proteins; Biological Transport; Calcium Signaling; Indoleacetic Acids; Microtubules; Mutation; Phosphotransferases; Plant Growth Regulators; Signal Transduction
PubMed: 32891072
DOI: 10.1111/tpj.14984 -
Cellular and Molecular Gastroenterology... 2022
Topics: Phosphotransferases (Alcohol Group Acceptor); Homeostasis; Gastrointestinal Tract
PubMed: 36162437
DOI: 10.1016/j.jcmgh.2022.09.001 -
FEBS Letters Jan 2022Cancer cells are challenged by a myriad of microenvironmental stresses, and it is their ability to efficiently adapt to the constantly changing nutrient, energy,... (Review)
Review
Cancer cells are challenged by a myriad of microenvironmental stresses, and it is their ability to efficiently adapt to the constantly changing nutrient, energy, oxidative, and/or immune landscape that allows them to survive and proliferate. Such adaptations, however, result in distinct vulnerabilities that are attractive therapeutic targets. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are a family of druggable stress-regulated phosphoinositide kinases that become conditionally essential as a metabolic adaptation, paving the way to targeting cancer cell dependencies. Further, PI5P4Ks have a synthetic lethal interaction with the tumor suppressor p53, the loss of which is one of the most prevalent genetic drivers of malignant transformation. PI5P4K's emergence as a crucial axis in the expanding landscape of phosphoinositide signaling in cancer has already stimulated the development of specific inhibitors. Thus, a better understanding of the biology of the PI5P4Ks will allow for targeted and effective therapeutic interventions. Here, we attempt to summarize the mounting roles of the PI5P4Ks in cancer, including evidence that targeting them is a therapeutic vulnerability and promising next-in-line treatment for multiple cancer subtypes.
Topics: Phosphotransferases (Alcohol Group Acceptor)
PubMed: 34822164
DOI: 10.1002/1873-3468.14237 -
Current Opinion in Chemical Biology Feb 2020Dynamical features of cell signaling are the essence of living organisms. To understand animal development, it is fundamental to investigate signaling dynamics in vivo.... (Review)
Review
Dynamical features of cell signaling are the essence of living organisms. To understand animal development, it is fundamental to investigate signaling dynamics in vivo. Robust reporters are required to visualize spatial and temporal dynamics of enzyme activities and protein-protein interactions involved in signaling pathways. In this review, we summarize recent development in the design of new classes of fluorescent reporters for imaging dynamic activities of proteases, kinases, and protein-protein interactions. These reporters operate on new physical and/or chemical principles; achieve large dynamic range, high brightness, and fast kinetics; and reveal spatiotemporal dynamics of signaling that is correlated with developmental events such as embryonic morphogenesis in live animals including Drosophila and zebrafish. Therefore, many of these reporters are great tools for biological discovery and mechanistic understanding of animal development and disease progression.
Topics: Animals; Fluorescent Dyes; Humans; Image Processing, Computer-Assisted; Optical Imaging; Peptide Hydrolases; Phosphotransferases; Protein Interaction Maps; Signal Transduction
PubMed: 31678813
DOI: 10.1016/j.cbpa.2019.09.004 -
Pain Apr 2015Existing analgesics are not efficacious in treating all patients with chronic pain and have harmful side effects when used long term. A deeper understanding of pain... (Review)
Review
Existing analgesics are not efficacious in treating all patients with chronic pain and have harmful side effects when used long term. A deeper understanding of pain signaling and sensitization could lead to the development of more efficacious analgesics. Nociceptor sensitization occurs under conditions of inflammation and nerve injury where diverse chemicals are released and signal through receptors to reduce the activation threshold of ion channels, leading to an overall increase in neuronal excitability. Drugs that inhibit specific receptors have so far been unsuccessful in alleviating pain, possibly because they do not simultaneously target the diverse receptors that contribute to nociceptor sensitization. Hence, the focus has shifted toward targeting downstream convergence points of nociceptive signaling. Lipid mediators, including phosphatidylinositol 4,5-bisphosphate (PIP2), are attractive targets, as these molecules are required for signaling downstream of G-protein-coupled receptors and receptor tyrosine kinases. Furthermore, PIP2 regulates the activity of various ion channels. Thus, PIP2 sits at a critical convergence point for multiple receptors, ion channels, and signaling pathways that promote and maintain chronic pain. Decreasing the amount of PIP2 in neurons was recently shown to attenuate pronociceptive signaling and could provide a novel approach for treating pain. Here, we review the lipid kinases that are known to regulate pain signaling and sensitization and speculate on which additional lipid kinases might regulate signaling in nociceptive neurons.
Topics: Animals; Chronic Pain; Humans; Lipid Metabolism; Nociception; Phosphotransferases; Signal Transduction
PubMed: 25789432
DOI: 10.1097/01.j.pain.0000460345.92588.4b -
Laboratory Investigation; a Journal of... Feb 2018Protein phosphorylation is the most common type of post-translational modification in eukaryotes. The phosphoproteome is defined as the complete set of experimentally... (Review)
Review
Protein phosphorylation is the most common type of post-translational modification in eukaryotes. The phosphoproteome is defined as the complete set of experimentally detectable phosphorylation sites present in a cell's proteome under various conditions. However, we are still far from identifying all the phosphorylation sites in a cell mainly due to the lack of information about phosphorylation events involving residues other than Ser, Thr and Tyr. Four types of phosphate-protein linkage exist and these generate nine different phosphoresidues-pSer, pThr, pTyr, pHis, pLys, pArg, pAsp, pGlu and pCys. Most of the effort in studying protein phosphorylation has been focused on Ser, Thr and Tyr phosphorylation. The recent development of 1- and 3-pHis monoclonal antibodies promises to increase our understanding of His phosphorylation and the kinases and phosphatases involved. Several His kinases are well defined in prokaryotes, especially those involved in two-component system (TCS) signaling. However, in higher eukaryotes, NM23, a protein originally characterized as a nucleoside diphosphate kinase, is the only characterized protein-histidine kinase. This ubiquitous and conserved His kinase autophosphorylates its active site His, and transfers this phosphate either onto a nucleoside diphosphate or onto a protein His residue. Studies of NM23 protein targets using newly developed anti-pHis antibodies will surely help illuminate the elusive His phosphorylation-based signaling pathways. This review discusses the role that the NM23/NME/NDPK phosphotransferase has, how the addition of the pHis phosphoproteome will expand the phosphoproteome and make His phosphorylation part of the global phosphorylation world. It also summarizes why our understanding of phosphorylation is still largely restricted to the acid stable phosphoproteome, and highlights the study of NM23 histidine kinase as an entrée into the world of histidine phosphorylation.
Topics: Animals; Eukaryotic Cells; Histidine Kinase; Humans; NM23 Nucleoside Diphosphate Kinases; Phosphoproteins; Phosphorylation; Phylogeny; Prokaryotic Cells; Proteome
PubMed: 29058706
DOI: 10.1038/labinvest.2017.118 -
Current Protocols in Nucleic Acid... Jun 2019This chemoenzymatic procedure describes a strategy for the preparation of 4'-thioribose nicotinamide adenine dinucleotide (S-NAD ), including chemical synthesis of...
This chemoenzymatic procedure describes a strategy for the preparation of 4'-thioribose nicotinamide adenine dinucleotide (S-NAD ), including chemical synthesis of nicotinamide 4'-riboside (S-NR), recombinant expression and purification of two NAD biosynthesis enzymes nicotinamide riboside kinase (NRK) and nicotinamide mononucleotide adenylyltransferase (NMNAT), and enzymatic synthesis of S-NAD . The first basic protocol describes the procedures for introduction of nicotinamide onto 4'-thioribose and subsequent deprotection to generate S-NR as the key intermediate for enzymatically synthesizing S-NAD . In the second basic protocol, experimental methods are detailed for the production of recombinant human NRK1 and NMNAT1 to catalyze conversion of S-NR to S-NAD . The third basic protocol presents the enzymatic approach for the generation of S-NAD from S-NR precursor. © 2019 by John Wiley & Sons, Inc.
Topics: Cloning, Molecular; Escherichia coli; Humans; NAD; Nicotinamide-Nucleotide Adenylyltransferase; Phosphotransferases (Alcohol Group Acceptor); Ribose; Sulfhydryl Compounds
PubMed: 30951610
DOI: 10.1002/cpnc.83 -
Science Advances Apr 2023Cells maintain a constant dialog between the extracellular matrix and their plasma membrane to fine tune signal transduction processes. We found that the receptor kinase...
Cells maintain a constant dialog between the extracellular matrix and their plasma membrane to fine tune signal transduction processes. We found that the receptor kinase FERONIA (FER), which is a proposed cell wall sensor, modulates phosphatidylserine plasma membrane accumulation and nano-organization, a key regulator of Rho GTPase signaling in Arabidopsis. We demonstrate that FER is required for both Rho-of-Plant 6 (ROP6) nano-partitioning at the membrane and downstream production of reactive oxygen species upon hyperosmotic stimulus. Genetic and pharmacological rescue experiments indicate that phosphatidylserine is required for a subset of, but not all, FER functions. Furthermore, application of FER ligand shows that its signaling controls both phosphatidylserine membrane localization and nanodomains formation, which, in turn, tunes ROP6 signaling. Together, we propose that a cell wall-sensing pathway controls via the regulation of membrane phospholipid content, the nano-organization of the plasma membrane, which is an essential cell acclimation to environmental perturbations.
Topics: Arabidopsis Proteins; Phosphatidylserines; Signal Transduction; Arabidopsis; Phosphotransferases; Cell Membrane; Plants
PubMed: 37027473
DOI: 10.1126/sciadv.add4791