Evidence map›Paper›PMID 25086086›Full record

ArticleMolecular pharmacology2014

Identification of protein kinase C activation as a novel mechanism for RGS2 protein upregulation through phenotypic screening of natural product extracts.

Avi Raveh, Pamela J Schultz, Lauren Aschermann, Colleen Carpenter, Giselle Tamayo-Castillo, Shugeng Cao, Jon Clardy, Richard R Neubig, David H Sherman, Benita Sjögren

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.

0numbers the graph read from it
0cells of the map it votes in
13citing papers in PubMed
1.3field-weighted citation impact, top 20% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

13 citing papers in PubMed, 24 citations in OpenAlex.

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  11. Untargeted Metabolomics To Ascertain Antibiotic Modes of Action.Antimicrobial agents and chemotherapy · 2016
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 6 institutions in 2 countries.

Avi RavehLife Sciences Institute, University of Michigan, Ann Arbor, Michigan (A.R., P.J.S., D.H.S.); Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan (L.A., R.R.N., B.S.); Department of Pharmacology (C.C.), Department of Medicinal Chemistry (D.H.S.), Department of Microbiology and Immunology (D.H.S.), Department of Chemistry (D.H.S.), Center for Chemical Genomics, University of Michigan, Ann Arbor, Michigan (D.H.S.); Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad, Santo Domingo de Heredia, Costa Rica & CIPRONA, Escuela de Química, Universidad de Costa Rica, San Pedro, Costa Rica (G.T-C.); Harvard Medical School, Boston, Massachusetts (S.C., J.C.); and University of Hawaii Cancer Center, Honolulu, Hawaii (S.C.).
Pamela J SchultzLife Sciences Institute, University of Michigan, Ann Arbor, Michigan (A.R., P.J.S., D.H.S.); Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan (L.A., R.R.N., B.S.); Department of Pharmacology (C.C.), Department of Medicinal Chemistry (D.H.S.), Department of Microbiology and Immunology (D.H.S.), Department of Chemistry (D.H.S.), Center for Chemical Genomics, University of Michigan, Ann Arbor, Michigan (D.H.S.); Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad, Santo Domingo de Heredia, Costa Rica & CIPRONA, Escuela de Química, Universidad de Costa Rica, San Pedro, Costa Rica (G.T-C.); Harvard Medical School, Boston, Massachusetts (S.C., J.C.); and University of Hawaii Cancer Center, Honolulu, Hawaii (S.C.).
Lauren AschermannLife Sciences Institute, University of Michigan, Ann Arbor, Michigan (A.R., P.J.S., D.H.S.); Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan (L.A., R.R.N., B.S.); Department of Pharmacology (C.C.), Department of Medicinal Chemistry (D.H.S.), Department of Microbiology and Immunology (D.H.S.), Department of Chemistry (D.H.S.), Center for Chemical Genomics, University of Michigan, Ann Arbor, Michigan (D.H.S.); Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad, Santo Domingo de Heredia, Costa Rica & CIPRONA, Escuela de Química, Universidad de Costa Rica, San Pedro, Costa Rica (G.T-C.); Harvard Medical School, Boston, Massachusetts (S.C., J.C.); and University of Hawaii Cancer Center, Honolulu, Hawaii (S.C.).
Colleen CarpenterLife Sciences Institute, University of Michigan, Ann Arbor, Michigan (A.R., P.J.S., D.H.S.); Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan (L.A., R.R.N., B.S.); Department of Pharmacology (C.C.), Department of Medicinal Chemistry (D.H.S.), Department of Microbiology and Immunology (D.H.S.), Department of Chemistry (D.H.S.), Center for Chemical Genomics, University of Michigan, Ann Arbor, Michigan (D.H.S.); Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad, Santo Domingo de Heredia, Costa Rica & CIPRONA, Escuela de Química, Universidad de Costa Rica, San Pedro, Costa Rica (G.T-C.); Harvard Medical School, Boston, Massachusetts (S.C., J.C.); and University of Hawaii Cancer Center, Honolulu, Hawaii (S.C.).
Giselle Tamayo-CastilloLife Sciences Institute, University of Michigan, Ann Arbor, Michigan (A.R., P.J.S., D.H.S.); Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan (L.A., R.R.N., B.S.); Department of Pharmacology (C.C.), Department of Medicinal Chemistry (D.H.S.), Department of Microbiology and Immunology (D.H.S.), Department of Chemistry (D.H.S.), Center for Chemical Genomics, University of Michigan, Ann Arbor, Michigan (D.H.S.); Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad, Santo Domingo de Heredia, Costa Rica & CIPRONA, Escuela de Química, Universidad de Costa Rica, San Pedro, Costa Rica (G.T-C.); Harvard Medical School, Boston, Massachusetts (S.C., J.C.); and University of Hawaii Cancer Center, Honolulu, Hawaii (S.C.).
Shugeng CaoLife Sciences Institute, University of Michigan, Ann Arbor, Michigan (A.R., P.J.S., D.H.S.); Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan (L.A., R.R.N., B.S.); Department of Pharmacology (C.C.), Department of Medicinal Chemistry (D.H.S.), Department of Microbiology and Immunology (D.H.S.), Department of Chemistry (D.H.S.), Center for Chemical Genomics, University of Michigan, Ann Arbor, Michigan (D.H.S.); Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad, Santo Domingo de Heredia, Costa Rica & CIPRONA, Escuela de Química, Universidad de Costa Rica, San Pedro, Costa Rica (G.T-C.); Harvard Medical School, Boston, Massachusetts (S.C., J.C.); and University of Hawaii Cancer Center, Honolulu, Hawaii (S.C.).
Jon ClardyLife Sciences Institute, University of Michigan, Ann Arbor, Michigan (A.R., P.J.S., D.H.S.); Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan (L.A., R.R.N., B.S.); Department of Pharmacology (C.C.), Department of Medicinal Chemistry (D.H.S.), Department of Microbiology and Immunology (D.H.S.), Department of Chemistry (D.H.S.), Center for Chemical Genomics, University of Michigan, Ann Arbor, Michigan (D.H.S.); Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad, Santo Domingo de Heredia, Costa Rica & CIPRONA, Escuela de Química, Universidad de Costa Rica, San Pedro, Costa Rica (G.T-C.); Harvard Medical School, Boston, Massachusetts (S.C., J.C.); and University of Hawaii Cancer Center, Honolulu, Hawaii (S.C.).
Richard R NeubigLife Sciences Institute, University of Michigan, Ann Arbor, Michigan (A.R., P.J.S., D.H.S.); Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan (L.A., R.R.N., B.S.); Department of Pharmacology (C.C.), Department of Medicinal Chemistry (D.H.S.), Department of Microbiology and Immunology (D.H.S.), Department of Chemistry (D.H.S.), Center for Chemical Genomics, University of Michigan, Ann Arbor, Michigan (D.H.S.); Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad, Santo Domingo de Heredia, Costa Rica & CIPRONA, Escuela de Química, Universidad de Costa Rica, San Pedro, Costa Rica (G.T-C.); Harvard Medical School, Boston, Massachusetts (S.C., J.C.); and University of Hawaii Cancer Center, Honolulu, Hawaii (S.C.).
David H ShermanLife Sciences Institute, University of Michigan, Ann Arbor, Michigan (A.R., P.J.S., D.H.S.); Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan (L.A., R.R.N., B.S.); Department of Pharmacology (C.C.), Department of Medicinal Chemistry (D.H.S.), Department of Microbiology and Immunology (D.H.S.), Department of Chemistry (D.H.S.), Center for Chemical Genomics, University of Michigan, Ann Arbor, Michigan (D.H.S.); Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad, Santo Domingo de Heredia, Costa Rica & CIPRONA, Escuela de Química, Universidad de Costa Rica, San Pedro, Costa Rica (G.T-C.); Harvard Medical School, Boston, Massachusetts (S.C., J.C.); and University of Hawaii Cancer Center, Honolulu, Hawaii (S.C.).
Benita SjögrenLife Sciences Institute, University of Michigan, Ann Arbor, Michigan (A.R., P.J.S., D.H.S.); Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan (L.A., R.R.N., B.S.); Department of Pharmacology (C.C.), Department of Medicinal Chemistry (D.H.S.), Department of Microbiology and Immunology (D.H.S.), Department of Chemistry (D.H.S.), Center for Chemical Genomics, University of Michigan, Ann Arbor, Michigan (D.H.S.); Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad, Santo Domingo de Heredia, Costa Rica & CIPRONA, Escuela de Química, Universidad de Costa Rica, San Pedro, Costa Rica (G.T-C.); Harvard Medical School, Boston, Massachusetts (S.C., J.C.); and University of Hawaii Cancer Center, Honolulu, Hawaii (S.C.) sjogren1@msu.edu.
University of Hawaiʻi at Mānoa · USCancer Center of Hawaii · USNational Biodiversity Institute · CRUniversity of Hawaii Cancer CenterUniversity of Hawaii System · USUniversity of Michigan–Ann Arbor · US

Funding

of Natural Product based Drugs and Bioenergetic Materials from Costa Rican BiotaU01TW007404 · FIC · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHERMAN, DAVID H · 2005 to 2013
$7.6M
FIC NIH HHS U01 TW007404
6 · The paper itself

Abstract

Biochemical high-throughput screening is widely used in drug discovery, using a variety of small molecule libraries. However, broader screening strategies may be more beneficial to identify novel biologic mechanisms. In the current study we used a β-galactosidase complementation method to screen a selection of microbial-derived pre-fractionated natural product extracts for those that increase regulator of G protein signaling 2 (RGS2) protein levels. RGS2 is a member of a large family of proteins that all regulate signaling through G protein-coupled receptors (GPCRs) by accelerating GTPase activity on active Gα as well as through other mechanisms. RGS2(-/-) mice are hypertensive, show increased anxiety, and are prone to heart failure. RGS2 has a very short protein half-life due to rapid proteasomal degradation, and we propose that enhancement of RGS2 protein levels could be a beneficial therapeutic strategy. Bioassay-guided fractionation of one of the hit strains yielded a pure compound, Indolactam V, a known protein kinase C (PKC) activator, which selectively increased RGS2 protein levels in a time- and concentration-dependent manner. Similar results were obtained with phorbol 12-myristate 13-acetate as well as activation of the Gq-coupled muscarinic M3 receptor. The effect on RGS2 protein levels was blocked by the nonselective PKC inhibitor Gö6983 (3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione), the PKCβ-selective inhibitor Ruboxastaurin, as well as small interfering RNA-mediated knockdown of PKCβ. Indolactam V-mediated increases in RGS2 protein levels also had functional effects on GPCR signaling. This study provides important proof-of-concept for our screening strategy and could define a negative feedback mechanism in Gq/Phospholipase C signaling through RGS2 protein upregulation.

Indexed as

Up-RegulationActinobacteriaAnimalsBiological ProductsHEK293 CellsHigh-Throughput Screening AssaysHumansIndolesLactamsMaleimidesMyocytes, Smooth MusclePhenotypeProtein Kinase C betaProtein Kinase InhibitorsRatsReceptor, Muscarinic M32-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimideBiological Productsindolactam VIndolesLactamsMaleimidesProtein Kinase C betaProtein Kinase InhibitorsReceptor, Muscarinic M3RGS2 protein, humanRGS4 proteinRGS ProteinsruboxistaurinSmall Molecule LibrariesTetradecanoylphorbol Acetate

Identifiers

PMID25086086
PMCPMC6067637
OpenAlexW2148520640

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.