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J Biol Chem, Vol. 273, Issue 7, 3848-3853, February 13, 1998
From the Division of Hematology, Washington University School of
Medicine, St. Louis, Missouri 63110
The effect of wortmannin on the trafficking of
the mannose 6-phosphate/insulin-like growth factor II receptor
(Man-6-P/IGF-II receptor) and its ligand 
-glucuronidase has been
determined in murine L cells and normal rat kidney cells. The drug
induced a 90% decrease in the steady-state level of the Man-6-P/IGF-II
receptor at the plasma membrane without affecting the rate of
internalization, indicating that the return of receptor from endosomes
to the plasma membrane is retarded. Wortmannin also slowed the movement
of receptor from endosomes to the trans-Golgi network by
about 60%. Such a kinetic block would dramatically reduce the number
of Man-6-P/IGF-II receptors in the trans-Golgi network,
which could account for the previously described hypersecretion of
procathepsin D induced by wortmannin. In addition, the drug slowed
delivery of endocytosed -glucuronidase from endosomes to dense
lysosomes. These data, taken together with the published reports of
others, indicate that wortmannin inhibits membrane trafficking out of
multiple compartments of the endosomal system and suggest a role for
phosphatidylinositol 3-kinase in regulating these processes.
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