Mannose-6-phosphate/insulin-like growth factor-II receptor is a receptor for retinoic acid.
Retinoic acid (RA) exerts diverse biological effects in the control of cell growth in embryogenesis and oncogenesis. These effects of RA are thought to be mediated by the nuclear retinoid receptors. Mannose-6-phosphate (M6P)/insulin-like growth factor-II (IGF-II) receptor is a multifunctional membrane glycoprotein that is known to bind both M6P and IGF-II and function primarily in the binding and trafficking of lysosomal enzymes, the activation of transforming growth factor-beta, and the degradation of IGF-II. M6P/IGF-II receptor has recently been implicated in fetal development and carcinogenesis. Despite the functional similarities between RA and the M6P/IGF-II receptor, no direct biochemical link has been established. Here, we show that the M6P/IGF-II receptor also binds RA with high affinity at a site that is distinct from those for M6P and IGF-II, as identified by a photoaffinity labeling technique. We also show that the binding of RA to the M6P/IGF-II receptor enhances the primary functions of this receptor. The biological consequence of the interaction appears to be the suppression of cell proliferation and/or induction of apoptosis. These findings suggest that the M6P/IGF-II receptor mediates a RA response pathway that is important in cell growth regulation. This discovery of the interaction of RA with the M6P/IGF-II receptor may have important implications for our understanding of the roles of RA and the M6P/IGF-II receptor in development, carcinogenesis, and lysosomal enzyme-related diseases.
Kang
J X
JX
Medical Services, Massachusetts General Hospital (East), 149 13th Street, Fourth Floor, Charlestown, MA 02129, USA. kang.jing@mgh.harvard.edu
Li
Y
Y
Leaf
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D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D002478:Cells, Cultured; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D007700:Kinetics; D008360:Mannosephosphates / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019920:Photoaffinity Labels; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000187:drug effects / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology
D001798:Blood Proteins; D008360:Mannosephosphates; D008565:Membrane Proteins; D019920:Photoaffinity Labels; D017527:Receptor, IGF Type 2; D018168:Receptors, Retinoic Acid; C027693:mannose-6-phosphate; D014212:Tretinoin; D007335:Insulin-Like Growth Factor II