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The intrinsically disordered region of the cytokinetic F-BAR protein Cdc15 performs a unique essential function in maintenance of cytokinetic ring integrity.
Mangione MC, Snider CE, Gould KL
(2019) Mol Biol Cell 30: 2790-2801
MeSH Terms: Cell Cycle Proteins, Cell Division, Cytokinesis, Cytoskeletal Proteins, GTP-Binding Proteins, Protein Domains, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, src Homology Domains
Show Abstract · Added March 3, 2020
Successful separation of two daughter cells (i.e., cytokinesis) is essential for life. Many eukaryotic cells divide using a contractile apparatus called the cytokinetic ring (CR) that associates dynamically with the plasma membrane (PM) and generates force that contributes to PM ingression between daughter cells. In important membrane-CR scaffolds include the paralogous F-BAR proteins Cdc15 and Imp2. Their conserved protein structure consists of the archetypal F-BAR domain linked to an SH3 domain by an intrinsically disordered region (IDR). Functions have been assigned to the F-BAR and SH3 domains. In this study we probed the function of the central IDR. We found that the IDR of Cdc15 is essential for viability and cannot be replaced by that of Imp2, whereas the F-BAR domain of Cdc15 can be swapped with several different F-BAR domains, including that of Imp2. Deleting part of the IDR results in CR defects and abolishes calcineurin phosphatase localization to the CR. Together these results indicate that Cdc15's IDR has a nonredundant essential function that coordinates regulation of CR architecture.
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9 MeSH Terms
Control of antiviral innate immune response by protein geranylgeranylation.
Yang S, Harding AT, Sweeney C, Miao D, Swan G, Zhou C, Jiang Z, Fitzgerald KA, Hammer G, Bergo MO, Kroh HK, Lacy DB, Sun C, Glogauer M, Que LG, Heaton NS, Wang D
(2019) Sci Adv 5: eaav7999
MeSH Terms: Adaptor Proteins, Signal Transducing, Alkyl and Aryl Transferases, Animals, Endoplasmic Reticulum, Female, Humans, Immunity, Innate, Macrophages, Alveolar, Male, Mice, Knockout, Neuropeptides, Orthomyxoviridae Infections, Protein Prenylation, Receptor-Interacting Protein Serine-Threonine Kinases, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, rac GTP-Binding Proteins, rac1 GTP-Binding Protein
Show Abstract · Added March 24, 2020
The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIP to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.
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18 MeSH Terms
GPCRs and Signal Transducers: Interaction Stoichiometry.
Gurevich VV, Gurevich EV
(2018) Trends Pharmacol Sci 39: 672-684
MeSH Terms: Animals, Arrestins, GTP-Binding Proteins, Humans, Receptors, G-Protein-Coupled, Signal Transduction
Show Abstract · Added March 18, 2020
Until the late 1990s, class A G protein-coupled receptors (GPCRs) were believed to function as monomers. Indirect evidence that they might internalize or even signal as dimers has emerged, along with proof that class C GPCRs are obligatory dimers. Crystal structures of GPCRs and their much larger binding partners were consistent with the idea that two receptors might engage a single G protein, GRK, or arrestin. However, recent biophysical, biochemical, and structural evidence invariably suggests that a single GPCR binds G proteins, GRKs, and arrestins. Here we review existing evidence of the stoichiometry of GPCR interactions with signal transducers and discuss potential biological roles of class A GPCR oligomers, including proposed homo- and heterodimers.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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α- and α-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.
Sánchez-Soto M, Casadó-Anguera V, Yano H, Bender BJ, Cai NS, Moreno E, Canela EI, Cortés A, Meiler J, Casadó V, Ferré S
(2018) Mol Neurobiol 55: 8438-8454
MeSH Terms: Adenylyl Cyclases, Animals, Cerebral Cortex, Clonidine, Dopamine, Extracellular Signal-Regulated MAP Kinases, GTP-Binding Proteins, HEK293 Cells, Humans, Idazoxan, Ligands, Neostriatum, Norepinephrine, Phosphorylation, Quinpirole, Receptors, Adrenergic, alpha-2, Receptors, Dopamine, Sheep, Tetrahydronaphthalenes
Show Abstract · Added March 21, 2020
The poor norepinephrine innervation and high density of Gi/o-coupled α- and α-adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D-like receptor ligands, such as the D receptor agonist 7-OH-PIPAT and the D receptor agonist RO-105824, to α-adrenoceptors in cortical and striatal tissue, which express α-adrenoceptors and both α- and α-adrenoceptors, respectively. The affinity of dopamine for α-adrenoceptors was found to be similar to that for D-like and D-like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α- and α-adrenoceptors. Their ability to activate Gi/o proteins through α- and α-adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α-adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α- and α-adrenoceptors was nearly identical to its binding to the crystallized D receptor. Therefore, we provide conclusive evidence that α- and α-adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D-like receptor ligands, which calls for revisiting previous studies with those ligands.
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G Protein Preassembly Rescues Efficacy of W Toggle Mutations in Neuropeptide Y Receptor.
Kaiser A, Hempel C, Wanka L, Schubert M, Hamm HE, Beck-Sickinger AG
(2018) Mol Pharmacol 93: 387-401
MeSH Terms: Amino Acid Sequence, Binding Sites, Dose-Response Relationship, Drug, GTP-Binding Proteins, HEK293 Cells, Humans, Mutation, Neuropeptide Y, Protein Structure, Secondary, Receptors, Neuropeptide Y
Show Abstract · Added March 24, 2020
Ligand binding and pathway-specific activation of G protein-coupled receptors is currently being studied with great effort. Individual answers may depend on the nature of the ligands and the effector pathway. Recently, we have presented a detailed model of neuropeptide Y bound to the YR. Accordingly, the C-terminal part of the peptide binds deeply in the transmembrane bundle and brings the side chain of the most essential Y in close proximity to W Here, we investigate the role of this interaction for ligand binding and activation of this receptor. BRET sensors were used for detailed investigation of effector coupling and led to the identification of preassembly of the YR-G complex. It further confirmed ligand-dependent recruitment of arrestin3. Using equally sensitive readouts for G activation and arrestin recruitment as well as quantification with operational models of agonism allowed us to identify a strong inherent bias for G activation over arrestin3 recruitment for the wild-type receptor. By systematic mutagenesis, we found that W does not contribute to the binding affinity, but acts as an allosteric connector to couple ligand binding to G activation and arrestin3 recruitment. However, even mutagenesis to a small threonine did not lead to a complete loss of signaling. Interestingly, signaling was restored to wild-type levels by ligands that contain a naphthylalanine as the C-terminal residue instead of Y Steric and polar contributions of W for the activation of the receptor are discussed in the context of different mechanisms of G protein coupling and arrestin recruitment.
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
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MeSH Terms
Cdk1-dependent phosphoinhibition of a formin-F-BAR interaction opposes cytokinetic contractile ring formation.
Willet AH, Bohnert KA, Gould KL
(2018) Mol Biol Cell 29: 713-721
MeSH Terms: Actin Cytoskeleton, Actins, CDC2 Protein Kinase, Cell Cycle Proteins, Cell Division, Cytokinesis, Cytoskeletal Proteins, GTP-Binding Proteins, Phosphorylation, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 14, 2018
In , cytokinesis requires the assembly and constriction of an actomyosin-based contractile ring (CR). A single essential formin, Cdc12, localizes to the cell middle upon mitotic onset and nucleates the F-actin of the CR. Cdc12 medial recruitment is mediated in part by its direct binding to the F-BAR scaffold Cdc15. Given that Cdc12 is hyperphosphorylated in M phase, we explored whether Cdc12 phosphoregulation impacts its association with Cdc15 during mitosis. We found that Cdk1, a major mitotic kinase, phosphorylates Cdc12 on six N-terminal residues near the Cdc15-binding site, and phosphorylation on these sites inhibits its interaction with the Cdc15 F-BAR domain. Consistent with this finding, a mutant with all six Cdk1 sites changed to phosphomimetic residues () displays phenotypes similar to , in which the Cdc15-binding motif is disrupted; both show reduced Cdc12 at the CR and delayed CR formation. Together, these results indicate that Cdk1 phosphorylation of formin Cdc12 antagonizes its interaction with Cdc15 and thereby opposes Cdc12's CR localization. These results are consistent with a general role for Cdk1 in inhibiting cytokinesis until chromosome segregation is complete.
© 2018 Willet et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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11 MeSH Terms
Non-visual arrestins regulate the focal adhesion formation via small GTPases RhoA and Rac1 independently of GPCRs.
Cleghorn WM, Bulus N, Kook S, Gurevich VV, Zent R, Gurevich EV
(2018) Cell Signal 42: 259-269
MeSH Terms: Actin Cytoskeleton, Animals, Cell Adhesion, Cell Line, Cell Movement, Fibroblasts, Focal Adhesions, Gene Expression Regulation, Mice, Neuropeptides, Receptors, G-Protein-Coupled, Signal Transduction, beta-Arrestin 1, beta-Arrestin 2, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, rho GTP-Binding Proteins
Show Abstract · Added March 14, 2018
Arrestins recruit a variety of signaling proteins to active phosphorylated G protein-coupled receptors in the plasma membrane and to the cytoskeleton. Loss of arrestins leads to decreased cell migration, altered cell shape, and an increase in focal adhesions. Small GTPases of the Rho family are molecular switches that regulate actin cytoskeleton and affect a variety of dynamic cellular functions including cell migration and cell morphology. Here we show that non-visual arrestins differentially regulate RhoA and Rac1 activity to promote cell spreading via actin reorganization, and focal adhesion formation via two distinct mechanisms. Arrestins regulate these small GTPases independently of G-protein-coupled receptor activation.
Copyright © 2017 Elsevier Inc. All rights reserved.
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17 MeSH Terms
RHOA GTPase Controls YAP-Mediated EREG Signaling in Small Intestinal Stem Cell Maintenance.
Liu M, Zhang Z, Sampson L, Zhou X, Nalapareddy K, Feng Y, Akunuru S, Melendez J, Davis AK, Bi F, Geiger H, Xin M, Zheng Y
(2017) Stem Cell Reports 9: 1961-1975
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Cell Cycle Proteins, Cell Differentiation, Cell Proliferation, Epiregulin, Epithelium, Gene Expression Regulation, Developmental, Intestine, Small, Mice, Mice, Knockout, Morphogenesis, Phosphoproteins, Stem Cells, Wnt Signaling Pathway, beta Catenin, rho GTP-Binding Proteins
Show Abstract · Added February 7, 2018
RHOA, a founding member of the Rho GTPase family, is critical for actomyosin dynamics, polarity, and morphogenesis in response to developmental cues, mechanical stress, and inflammation. In murine small intestinal epithelium, inducible RHOA deletion causes a loss of epithelial polarity, with disrupted villi and crypt organization. In the intestinal crypts, RHOA deficiency results in reduced cell proliferation, increased apoptosis, and a loss of intestinal stem cells (ISCs) that mimic effects of radiation damage. Mechanistically, RHOA loss reduces YAP signaling of the Hippo pathway and affects YAP effector epiregulin (EREG) expression in the crypts. Expression of an active YAP (S112A) mutant rescues ISC marker expression, ISC regeneration, and ISC-associated Wnt signaling, but not defective epithelial polarity, in RhoA knockout mice, implicating YAP in RHOA-regulated ISC function. EREG treatment or active β-catenin Catnb mutant expression rescues the RhoA KO ISC phenotypes. Thus, RHOA controls YAP-EREG signaling to regulate intestinal homeostasis and ISC regeneration.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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17 MeSH Terms
Identification and Characterization of the First Selective Y Receptor Positive Allosteric Modulator.
Schubert M, Stichel J, Du Y, Tough IR, Sliwoski G, Meiler J, Cox HM, Weaver CD, Beck-Sickinger AG
(2017) J Med Chem 60: 7605-7612
MeSH Terms: Allosteric Regulation, Animals, Arrestins, COS Cells, Chlorocebus aethiops, Cyclohexanols, GTP-Binding Proteins, HEK293 Cells, Humans, Models, Molecular, Receptors, Neuropeptide Y, Signal Transduction
Show Abstract · Added March 17, 2018
The human Y receptor (YR) and its cognate ligand, pancreatic polypeptide (PP), are involved in the regulation of energy expenditure, satiety, and food intake. This system represents a potential target for the treatment of metabolic diseases and has been extensively investigated and validated in vivo. Here, we present the compound tBPC (tert-butylphenoxycyclohexanol), a novel and selective YR positive allosteric modulator that potentiates YR activation in G-protein signaling and arrestin3 recruitment experiments. The compound has no effect on the binding of the orthosteric ligands, implying its allosteric mode of action at the YR and evidence for a purely efficacy-driven positive allosteric modulation. Finally, the ability of tBPC to selectively potentiate YR agonism initiated by PP was confirmed in mouse descending colon mucosa preparations expressing native YR, demonstrating YR positive allosteric modulation in vitro.
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12 MeSH Terms
Phosphoinositide-mediated ring anchoring resists perpendicular forces to promote medial cytokinesis.
Snider CE, Willet AH, Chen JS, Arpağ G, Zanic M, Gould KL
(2017) J Cell Biol 216: 3041-3050
MeSH Terms: 1-Phosphatidylinositol 4-Kinase, Cell Cycle Proteins, Cytokinesis, GTP-Binding Proteins, Glycosylphosphatidylinositols, Myosin Type V, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 14, 2018
Many eukaryotic cells divide by assembling and constricting an actin- and myosin-based contractile ring (CR) that is physically linked to the plasma membrane (PM). In this study, we report that cells lacking , which encodes a conserved PM scaffold for the phosphatidylinositol-4 kinase Stt4, build CRs that can slide away from the cell middle during anaphase in a myosin V-dependent manner. The Efr3-dependent CR-anchoring mechanism is distinct from previously reported pathways dependent on the Fes/CIP4 homology Bin-Amphiphysin-Rvs167 (F-BAR) protein Cdc15 and paxillin Pxl1. In , the concentrations of several membrane-binding proteins were reduced in the CR and/or on the PM. Our results suggest that proper PM lipid composition is important to stabilize the central position of the CR and resist myosin V-based forces to promote the fidelity of cell division.
© 2017 Snider et al.
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8 MeSH Terms