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 inhibition of accurate targeting 
to lysosomes at 10-20 nM. Kinetic analysis indicated that a late Golgi (TGN) 
step was affected, and that other constitutive vesicular transport events were 
not. The M6P recognition signal was still generated in the presence of 
wortmannin suggesting that the drug was directly inhibiting export of the 
receptor-ligand complex from the TGN, while removal of the drug led to a rapid 
restoration of accurate sorting. At the concentrations used, wortmannin and 
LY294002 are presently accepted to be specific inhibitors of PI3-K. I conclude 
that these data implicate such an enzyme in the trafficking of 
M6P-receptor-ligand complexes from the TGN towards lysosomes.