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Inhibition of endosome fusion by wortmannin persists in the presence of activated rab5

Jones, Arwyn Tomos ORCID: https://orcid.org/0000-0003-2781-8905, Mills, Ian G., Scheidig, Axel J., Alexandrov, Kirill and Clague, Michael J. 1998. Inhibition of endosome fusion by wortmannin persists in the presence of activated rab5. Molecular Biology of the Cell 9 (2) , pp. 323-332. 10.1091/mbc.9.2.323

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Abstract

Rab5-dependent endosome fusion is sensitive to the phosphoinositide 3-kinase inhibitor, wortmannin. It has been proposed that phosphoinositide 3-kinase activity may be required for activation of rab5 by influencing its nucleotide cycle such as to promote its active GTP state. In this report we demonstrate that endosome fusion remains sensitive to wortmannin despite preloading of endosomes with stimulatory levels of a GTPase-defective mutant rab5Q79L or of a xanthosine triphosphate-binding mutant, rab5D136N, in the presence of the nonhydrolysable analogue XTPγS. These results suggest that activation of rab5 cannot be the principal function of the wortmannin-sensitive factor on the endosome fusion pathway. This result is extrapolated to all GTPases by demonstrating that endosome fusion remains wortmannin sensitive despite prior incubation with the nonhydrolysable nucleotide analogue GTPγS. Consistent with these results, direct measurement of clathrin-coated vesicle-stimulated nucleotide dissociation from exogenous rab5 was insensitive to the presence of wortmannin. A large excess of rab5Q79L, beyond levels required for maximal stimulation of the fusion assay, afforded protection against wortmannin inhibition, and partial protection was also observed with an excess of wild-type rab5 independent of GTPγS.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Publisher: American Society for Cell Biology
ISSN: 1059-1524
Date of Acceptance: 1997
Last Modified: 27 Oct 2022 09:19
URI: https://orca.cardiff.ac.uk/id/eprint/65233

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