RanGAP1 Induces GTPase Activity of Nuclear Ras-related Ran

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1994 Mar 29

PMID 8146159

Citations 236

Authors

F R Bischoff

C Klebe

J Kretschmer

A Wittinghofer

H Ponstingl

Affiliations

Soon will be listed here.

Abstract

The nuclear Ras-related protein Ran binds guanine nucleotide and is involved in cell cycle regulation. Models of the signal pathway predict Ran to be active as Ran.GTP at the initiation of S phase upon activation by the nucleotide exchange factor RCC1 and to be inactivated for the onset of mitosis by hydrolysis of bound GTP. Here a nuclear homodimeric 65-kDa protein, RanGAP1, is described, which we believe to be the immediate antagonist of RCC1. It was purified from HeLa cell lysates and induces GTPase activity of Ran, but not Ras, by more than 3 orders of magnitude. The Ran mutant Q69L, modeled after RasQ61L, which is unable to hydrolyze bound GTP, is insensitive to RanGAP1.

Citing Articles

Structural basis for a nucleoporin exportin complex between RanBP2, SUMO1-RanGAP1, the E2 Ubc9, Crm1 and the Ran GTPase.

Baytshtok V, DiMattia M, Lima C bioRxiv. 2025; .

PMID: 39763778 PMC: 11703149. DOI: 10.1101/2024.10.04.616749.

CCDC69 maintains genome integrity by regulating KIF2C/MCAK depolymerase activity and the stability of the chromosomal passenger complex.

Fesquet D, Rabeharivelo G, van Dijk J, Prigent C, Morin N, Rouquier S Sci Rep. 2024; 14(1):30401.

PMID: 39638803 PMC: 11621681. DOI: 10.1038/s41598-024-81022-9.

The pro-oncogenic noncanonical activity of a RAS•GTP:RanGAP1 complex facilitates nuclear protein export.

Tripathi B, Hirsh N, Qian X, Durkin M, Wang D, Papageorge A Nat Cancer. 2024; 5(12):1902-1918.

PMID: 39528835 PMC: 11663792. DOI: 10.1038/s43018-024-00847-5.

Interphase chromosome conformation is specified by distinct folding programs inherited via mitotic chromosomes or through the cytoplasm.

Schooley A, Venev S, Aksenova V, Navarrete E, Dasso M, Dekker J bioRxiv. 2024; .

PMID: 39345587 PMC: 11429855. DOI: 10.1101/2024.09.16.613305.

Multiple types of nuclear localization signals in .

Canela-Perez I, Azuara-Liceaga E, Cuellar P, Saucedo-Cardenas O, Valdes J Biochem Biophys Rep. 2024; 39:101770.

PMID: 39055170 PMC: 11269297. DOI: 10.1016/j.bbrep.2024.101770.

References

Forrester W, Stutz F, Rosbash M, Wickens M . Defects in mRNA 3'-end formation, transcription initiation, and mRNA transport associated with the yeast mutation prp20: possible coupling of mRNA processing and chromatin structure. Genes Dev. 1992; 6(10):1914-26. DOI: 10.1101/gad.6.10.1914. View

Ren M, Drivas G, DEustachio P, Rush M . Ran/TC4: a small nuclear GTP-binding protein that regulates DNA synthesis. J Cell Biol. 1993; 120(2):313-23. PMC: 2119524. DOI: 10.1083/jcb.120.2.313. View

Belhumeur P, Lee A, Tam R, DiPaolo T, Fortin N, Clark M . GSP1 and GSP2, genetic suppressors of the prp20-1 mutant in Saccharomyces cerevisiae: GTP-binding proteins involved in the maintenance of nuclear organization. Mol Cell Biol. 1993; 13(4):2152-61. PMC: 359536. DOI: 10.1128/mcb.13.4.2152-2161.1993. View

Kadowaki T, Goldfarb D, Spitz L, Tartakoff A, Ohno M . Regulation of RNA processing and transport by a nuclear guanine nucleotide release protein and members of the Ras superfamily. EMBO J. 1993; 12(7):2929-37. PMC: 413547. DOI: 10.1002/j.1460-2075.1993.tb05955.x. View

Moore M, Blobel G . The GTP-binding protein Ran/TC4 is required for protein import into the nucleus. Nature. 1993; 365(6447):661-3. DOI: 10.1038/365661a0. View

Klebe C, Nishimoto T, Wittinghofer F . Functional expression in Escherichia coli of the mitotic regulator proteins p24ran and p45rcc1 and fluorescence measurements of their interaction. Biochemistry. 1993; 32(44):11923-8. DOI: 10.1021/bi00095a023. View

Sazer S, Nurse P . A fission yeast RCC1-related protein is required for the mitosis to interphase transition. EMBO J. 1994; 13(3):606-15. PMC: 394850. DOI: 10.1002/j.1460-2075.1994.tb06298.x. View

Leupold C, Goody R, Wittinghofer A . Stereochemistry of the elongation factor Tu X GTP complex. Eur J Biochem. 1983; 135(2):237-41. DOI: 10.1111/j.1432-1033.1983.tb07643.x. View

Tucker J, Sczakiel G, Feuerstein J, John J, Goody R, Wittinghofer A . Expression of p21 proteins in Escherichia coli and stereochemistry of the nucleotide-binding site. EMBO J. 1986; 5(6):1351-8. PMC: 1166947. DOI: 10.1002/j.1460-2075.1986.tb04366.x. View

10.

Ohtsubo M, Okazaki H, Nishimoto T . The RCC1 protein, a regulator for the onset of chromosome condensation locates in the nucleus and binds to DNA. J Cell Biol. 1989; 109(4 Pt 1):1389-97. PMC: 2115805. DOI: 10.1083/jcb.109.4.1389. View

11.

Drivas G, Shih A, Coutavas E, Rush M, DEustachio P . Characterization of four novel ras-like genes expressed in a human teratocarcinoma cell line. Mol Cell Biol. 1990; 10(4):1793-8. PMC: 362288. DOI: 10.1128/mcb.10.4.1793-1798.1990. View

12.

Bischoff F, Maier G, Tilz G, Ponstingl H . A 47-kDa human nuclear protein recognized by antikinetochore autoimmune sera is homologous with the protein encoded by RCC1, a gene implicated in onset of chromosome condensation. Proc Natl Acad Sci U S A. 1990; 87(21):8617-21. PMC: 55008. DOI: 10.1073/pnas.87.21.8617. View

13.

Frasch M . The maternally expressed Drosophila gene encoding the chromatin-binding protein BJ1 is a homolog of the vertebrate gene Regulator of Chromatin Condensation, RCC1. EMBO J. 1991; 10(5):1225-36. PMC: 452777. DOI: 10.1002/j.1460-2075.1991.tb08064.x. View

14.

Nishitani H, Ohtsubo M, Yamashita K, Iida H, Pines J, Yasudo H . Loss of RCC1, a nuclear DNA-binding protein, uncouples the completion of DNA replication from the activation of cdc2 protein kinase and mitosis. EMBO J. 1991; 10(6):1555-64. PMC: 452820. DOI: 10.1002/j.1460-2075.1991.tb07675.x. View

15.

Matsumoto T, Beach D . Premature initiation of mitosis in yeast lacking RCC1 or an interacting GTPase. Cell. 1991; 66(2):347-60. DOI: 10.1016/0092-8674(91)90624-8. View

16.

Bischoff F, Ponstingl H . Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1. Nature. 1991; 354(6348):80-2. DOI: 10.1038/354080a0. View

17.

Bischoff F, Ponstingl H . Mitotic regulator protein RCC1 is complexed with a nuclear ras-related polypeptide. Proc Natl Acad Sci U S A. 1991; 88(23):10830-4. PMC: 53025. DOI: 10.1073/pnas.88.23.10830. View

18.

Nice E, Fabri L, Hammacher A, Holden J, Simpson R, Burgess A . The purification of a Rap1 GTPase-activating protein from bovine brain cytosol. J Biol Chem. 1992; 267(3):1546-53. View

19.

Gideon P, John J, Frech M, Lautwein A, Clark R, Scheffler J . Mutational and kinetic analyses of the GTPase-activating protein (GAP)-p21 interaction: the C-terminal domain of GAP is not sufficient for full activity. Mol Cell Biol. 1992; 12(5):2050-6. PMC: 364376. DOI: 10.1128/mcb.12.5.2050-2056.1992. View

20.

Settleman J, Narasimhan V, Foster L, Weinberg R . Molecular cloning of cDNAs encoding the GAP-associated protein p190: implications for a signaling pathway from ras to the nucleus. Cell. 1992; 69(3):539-49. DOI: 10.1016/0092-8674(92)90454-k. View