Retinoic acid alters the intracellular trafficking of the mannose-6-phosphate/insulin-like growth factor II receptor and lysosomal enzymes.
Previously, we showed that retinoic acid (RA) binds to the mannose-6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) with high affinity, suggesting that M6P/IGF2R may be a receptor for RA. Here, we show that RA, after 2-3 h of incubation with cultured neonatal-rat cardiac fibroblasts, dramatically alters the intracellular distribution of M6P/IGF2R as well as that of cathepsin B (a lysosomal protease bearing M6P). Immunofluorescence techniques indicate that this change in intracellular distribution is characterized by a shift of the proteins from the perinuclear area to cytoplasmic vesicles. The effect of RA was neither blocked by an RA nuclear receptor antagonist (AGN193109) nor mimicked by a selective RA nuclear-receptor agonist (TTNPB). Furthermore, the RA-induced translocation of cathepsin B was not observed in M6P/IGF2R-deficient P388D1 cells but occurred in stably transfected P388D1 cells expressing the receptor, suggesting that the effect of RA might be the result of direct interaction with M6P/IGF2R, rather than the result of binding to the nuclear receptors. These observations not only support the idea that M6P/IGF2R mediates an RA-response pathway but also indicate a role for RA in control of intracellular trafficking of lysosomal enzymes. Therefore, our observations may have important implications for the understanding of the diverse biological effects of retinoids.
Kang
J X
JX
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. kang.jing@mgh.harvard.edu
Bell
J
J
Leaf
A
A
Beard
R L
RL
Chandraratna
R A
RA
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007641:Keratolytic Agents / Q000378:metabolism* / Q000494:pharmacology*; D008247:Lysosomes / Q000201:enzymology; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology*
D007641:Keratolytic Agents; D017527:Receptor, IGF Type 2; D014212:Tretinoin