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Wortmannin causes mistargeting of procathepsin D. Evidence for the involvement of a phosphatidylinositol 3-kinase in vesicular transport to lysosomes

By Howard W. Davidson

Abstract

Abstract. At present little is known of the biochemical machinery controlling transport of newly synthesized lysosomal hydrolases from the trans-Golgi network (TGN) to endosomes. The demonstration that Vps34p (a protein required for targeting soluble hydrolases to the vacuole in Saccharomyces cerevisiae) is a phosphatidylinositol 3-kinase (PI3-K) suggested the possibility that a homologous enzyme might be involved in the equivalent step in mammalian cells. Using the PI3-K inhibitors wortmannin and LY294002, I provide evidence to support this hypothesis. Treatment of K-562 cells with wortmannin induced secretion of procathepsin D, with half-maximal inhibi-I N most mammalian cells, transport of newly synthesized soluble acid hydrolases to lysosomes depends upon their recognition by receptors specific for mannose 6-phosphate (M6P) 1 residues, and their subsequent sequestration into clathrin-coated regions of the trans-Golgi Network (TGN) (for reviews see von Figura and Hasilik, 1986; Kornfeld and Mellman, 1989). The M6P modification appears unique to lysosomal hydrolases, and is formed by the concerted action of two enzymes, the first of which (UDP-GIcNAc: lysosomal enzyme N-acetylglucosamine-1phosphotransferase) recognizes conformation-dependent protein determinants in the lysosomal enzyme (Baranski et al., 1991). Phosphorylation begins before export of the hydrolase from the endoplasmic reticulum, but continues during the passage of the protein through the Golgi apparatu

Year: 1995
DOI identifier: 10.1083/jcb.130.4.797
OAI identifier: oai:CiteSeerX.psu:10.1.1.334.4577
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