Resistance to inhibitors of cholinesterase 8A catalyzes release of Gαi-GTP and nuclear mitotic apparatus protein (NuMA) from NuMA/LGN/Gαi-GDP complexes

Gregory G. Tall, Alfred G. Gilman

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Resistance to inhibitors of cholinesterase (Ric) 8A is a guanine nucleotide exchange factor that activates certain G protein α-subunits. Genetic studies in Caenorhabditis elegans and Drosophila melanogaster have placed RIC-8 in a previously uncharacterized G protein signaling pathway that regulates centrosome movements during cell division. Components of this pathway include G protein subunits of the Gαi class, GPR or GoLoco domain-containing proteins, RGS (regulator of G protein signaling) proteins, and accessory factors. These proteins interact to regulate microtubule pulling forces during mitotic movement of chromosomes. It is unclear how the GTP-binding and hydrolysis cycle of Gαi functions in the context of this pathway. In mammals, the GoLoco domain-containing protein LGN (GPSM2), the LGN- and microtubule-binding nuclear mitotic apparatus protein (NuMA), and Gαi regulate a similar process. We find that mammalian Ric-8A dissociates Gαi-GDP/LGN/NuMA complexes catalytically, releasing activated Gαi-GTP in vitro. Ric-8A-stimulated activation of Gαi caused concomitant liberation of NuMA from LGN. We conclude that Ric-8A efficiently utilizes GoLoco/Gαi-GDP complexes as substrates in vitro and suggest that Ric-8A-stimulated release of Gαi-GTP and/or NuMA regulates the microtubule pulling forces on centrosomes during cell division.

Original languageEnglish (US)
Pages (from-to)16584-16589
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number46
DOIs
StatePublished - Nov 15 2005

Fingerprint

Spindle Apparatus
Cholinesterase Inhibitors
Nuclear Proteins
Guanosine Triphosphate
Centrosome
Proteins
GTP-Binding Proteins
Microtubules
Cell Division
RGS Proteins
Gi-Go GTP-Binding Protein alpha Subunits
Microtubule Proteins
Guanine Nucleotide Exchange Factors
Caenorhabditis elegans
Protein Subunits
Drosophila melanogaster
Mammals
Hydrolysis
Chromosomes

Keywords

  • Cell division
  • G protein
  • GoLoco
  • GPR
  • Guanine nucleotide exchange

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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title = "Resistance to inhibitors of cholinesterase 8A catalyzes release of Gαi-GTP and nuclear mitotic apparatus protein (NuMA) from NuMA/LGN/Gαi-GDP complexes",
abstract = "Resistance to inhibitors of cholinesterase (Ric) 8A is a guanine nucleotide exchange factor that activates certain G protein α-subunits. Genetic studies in Caenorhabditis elegans and Drosophila melanogaster have placed RIC-8 in a previously uncharacterized G protein signaling pathway that regulates centrosome movements during cell division. Components of this pathway include G protein subunits of the Gαi class, GPR or GoLoco domain-containing proteins, RGS (regulator of G protein signaling) proteins, and accessory factors. These proteins interact to regulate microtubule pulling forces during mitotic movement of chromosomes. It is unclear how the GTP-binding and hydrolysis cycle of Gαi functions in the context of this pathway. In mammals, the GoLoco domain-containing protein LGN (GPSM2), the LGN- and microtubule-binding nuclear mitotic apparatus protein (NuMA), and Gαi regulate a similar process. We find that mammalian Ric-8A dissociates Gαi-GDP/LGN/NuMA complexes catalytically, releasing activated Gαi-GTP in vitro. Ric-8A-stimulated activation of Gαi caused concomitant liberation of NuMA from LGN. We conclude that Ric-8A efficiently utilizes GoLoco/Gαi-GDP complexes as substrates in vitro and suggest that Ric-8A-stimulated release of Gαi-GTP and/or NuMA regulates the microtubule pulling forces on centrosomes during cell division.",
keywords = "Cell division, G protein, GoLoco, GPR, Guanine nucleotide exchange",
author = "Tall, {Gregory G.} and Gilman, {Alfred G.}",
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T1 - Resistance to inhibitors of cholinesterase 8A catalyzes release of Gαi-GTP and nuclear mitotic apparatus protein (NuMA) from NuMA/LGN/Gαi-GDP complexes

AU - Tall, Gregory G.

AU - Gilman, Alfred G.

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N2 - Resistance to inhibitors of cholinesterase (Ric) 8A is a guanine nucleotide exchange factor that activates certain G protein α-subunits. Genetic studies in Caenorhabditis elegans and Drosophila melanogaster have placed RIC-8 in a previously uncharacterized G protein signaling pathway that regulates centrosome movements during cell division. Components of this pathway include G protein subunits of the Gαi class, GPR or GoLoco domain-containing proteins, RGS (regulator of G protein signaling) proteins, and accessory factors. These proteins interact to regulate microtubule pulling forces during mitotic movement of chromosomes. It is unclear how the GTP-binding and hydrolysis cycle of Gαi functions in the context of this pathway. In mammals, the GoLoco domain-containing protein LGN (GPSM2), the LGN- and microtubule-binding nuclear mitotic apparatus protein (NuMA), and Gαi regulate a similar process. We find that mammalian Ric-8A dissociates Gαi-GDP/LGN/NuMA complexes catalytically, releasing activated Gαi-GTP in vitro. Ric-8A-stimulated activation of Gαi caused concomitant liberation of NuMA from LGN. We conclude that Ric-8A efficiently utilizes GoLoco/Gαi-GDP complexes as substrates in vitro and suggest that Ric-8A-stimulated release of Gαi-GTP and/or NuMA regulates the microtubule pulling forces on centrosomes during cell division.

AB - Resistance to inhibitors of cholinesterase (Ric) 8A is a guanine nucleotide exchange factor that activates certain G protein α-subunits. Genetic studies in Caenorhabditis elegans and Drosophila melanogaster have placed RIC-8 in a previously uncharacterized G protein signaling pathway that regulates centrosome movements during cell division. Components of this pathway include G protein subunits of the Gαi class, GPR or GoLoco domain-containing proteins, RGS (regulator of G protein signaling) proteins, and accessory factors. These proteins interact to regulate microtubule pulling forces during mitotic movement of chromosomes. It is unclear how the GTP-binding and hydrolysis cycle of Gαi functions in the context of this pathway. In mammals, the GoLoco domain-containing protein LGN (GPSM2), the LGN- and microtubule-binding nuclear mitotic apparatus protein (NuMA), and Gαi regulate a similar process. We find that mammalian Ric-8A dissociates Gαi-GDP/LGN/NuMA complexes catalytically, releasing activated Gαi-GTP in vitro. Ric-8A-stimulated activation of Gαi caused concomitant liberation of NuMA from LGN. We conclude that Ric-8A efficiently utilizes GoLoco/Gαi-GDP complexes as substrates in vitro and suggest that Ric-8A-stimulated release of Gαi-GTP and/or NuMA regulates the microtubule pulling forces on centrosomes during cell division.

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KW - Guanine nucleotide exchange

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