Mannose-6-phosphate/insulin-like growth factor-II receptor is a receptor for retinoic acid

Abstract

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-β, 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.

Mannose 6-Phosphate/Insulin-like Growth Factor 2 Receptor Limits Cell Invasion by Controlling αVβ3 Integrin Expression and Proteolytic Processing of Urokinase-type Plasminogen Activator Receptor

“…Second, the lack of M6P/IGF2R in tumor cells may also contribute to their higher invasiveness due to impaired intracellular trafficking of cathepsins (Lorenzo et al, 2000), observed also in M6P/ IGF2R-deficient cell lines (Kasper et al, 1996). Third, some of the M6P/IGF2R's ligands, such as retinoic acid and granzyme B, were shown to induce apoptosis via the receptor (Kang et al, 1997;Motyka et al, 2000). Fourth, the loss of M6P/IGF2R may reduce the availability of active transforming growth factor (TGF)-␤ and thus its inhibitory effects on cell proliferation (Dennis and Rifkin, 1991;Godar et al, 1999;Leksa et al, 2005).…”

Real Time Kinetics of Insulin-like Growth Factor II (IGF-II) Interaction with the IGF-II/Mannose 6-Phosphate Receptor

“…IGF-IIR also interacts with the mannose 6-phosphate groups of glycosylated latent transforming growth factor-␤1 (lTGF-␤1), leading to removal of the side chains and activation to TGF-␤1, a growth inhibitor (15,16). IGF-IIR also binds retinoic acid and urokinase-type plasminogen activator receptor, but the specific function and position of binding is not known (17,18). Recently, it was shown that the uptake of granzyme B in T cell-mediated cell death was dependent upon IGF-IIR, and it is suggested that IGF-IIR is the receptor for cytotoxic T-cell-induced cell death (1).…”

Retinoic acid inhibits the infectivity and growth of Chlamydia pneumoniae in epithelial and endothelial cells through different receptors

“…Specifically, phosphomannosylated residues such as mannose-6P that specifically bind to this receptor and all-trans-retinoic acid (ATRA), which has a separate binding site on the M6P/IGF2 receptor [9], competitively inhibit C. pneumoniae infectivity and removal of the glycan decrease infectivity in vitro and in mouse models of lung infection [10,11].…”