Mannose 6-Phosphate Receptor Targeting and its Applications in Human Diseases

Gary‐Bobo, Magali; Nirdé, Philippe; Jeanjean, Audrey; Morère, Alaih; Garcia, Marcel

doi:10.2174/092986707782794005

Cited by 160 publications

(120 citation statements)

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“…Finally, FL-9b displayed rapid cellular uptake on the MCF-7 breast cancer cell line, known to overexpress a significant amount of CI-MPR receptors. 6 Figure 9) which correlates well with the increased M6P receptors present on MCF-7 cells. This again suggests that M6P-GP is likely uptaken by the overexpressed CI-MPR receptors present on the MCF-7 cell surface and subsequently transferred into the lysosomes.…”

supporting

confidence: 72%

Controlled Synthesis of End-Functionalized Mannose-6-phosphate Glycopolypeptides for Lysosome Targeting

et al. 2016

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The ubiquitous expression of the mannose-6-phosphate receptor on the majority of human cells makes it a valid target in the quest to deliver therapeutics selectively to the lysosome. In this work end-functionalized polyvalent mannose-6-phosphate glycopolypeptides (M6P-GPs) with high molecular weights (up to 22 kDa) have been synthesized via NCA polymerization. These synthetic M6P-GPs were found to display minimal toxicity to cells in vitro and show exceptional selectivity for trafficking into lysosomes in various cell lines. Comparison of the cellular uptake behavior of M6P-GP and the corresponding mannose-GP polymer reveals that incorporation of the phosphate moiety at the 6-position of mannose completely alters its trafficking behavior and becomes exclusively lysosome specific. We also demonstrate that trafficking of M6P-GPs in mammalian cells is likely associated with the CI-MPR receptor pathway. I n mammalian cells, mannose-6-phosphate receptors play a critical role in the sorting of lysosomal enzymes from secretory proteins and their subsequent delivery into lysosomes. 1 These receptors, which include the ∼300 kDa insulin-like growth factor-II (IGF-II)/cation-independent (CI) multifunctional transmembrane glycoprotein mannose-6-phosphate (M6P) receptor (CI-MPR), bind lysosomal enzymes containing phosphomannosyl residues in the trans-golgi network (TGN) and transport them to endosomes where the low pH leads to the dissociation of the ligand−receptor complex. 2 The receptors then return to the TGN to repeat another round of this process. As a result, the receptor CI-MPR is largely localized in the intracellular compartments and shuttles between TGN and endosomes with ∼10% of the receptor being present on the cell surface. 3 Additionally, the CI-MPR receptor is overexpressed in the early stage of several cancers, particularly in breast and prostate cancer, and hence can serve as an early marker for these cancers. 4,5 The ability of CI-MPR to deliver cargo specifically to the lysosome can thus be selectively targeted using M6P-labeled carriers to dispatch cytotoxic drugs inside lysosomes for destroying cancer cells. 6−8 In addition, CI-MPR can be targeted to deliver M6P-labeled enzymes into lysosomes for enzyme replacement therapies (ERTs) in non-neural lysosomal storage disorders (LSDs). 9,10 LSDs are a group of more than 40 metabolic disorders that result from the deficient activity of specific lysosomal enzymes inside the lysosomes leading to progressive accumulation of its substrate inside the cell. Nowadays several M6P-modified enzymes are used clinically for the treatment of LSD. However, the low levels of M6P modification dramatically reduce its binding efficiency to the receptor, and hence relatively high doses of these enzymes need to be administered to achieve significant therapeutic efficacy. 11 Modification of lysosomal enzymes with higher amounts of M6P residues for enhanced targeted delivery remains a critical challenge. 12 Previous studies demonstrate that CI-MPR exists as a dimer in the membrane ...

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confidence: 72%

Controlled Synthesis of End-Functionalized Mannose-6-phosphate Glycopolypeptides for Lysosome Targeting

et al. 2016

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“…transforming growth factor-␤) and pathogenic organisms (e.g. varicella-zoster virus) (60,61), which interact with the CI-MPR in a Man-6-P-dependent manner suggests numerous potential therapeutic applications.…”

Section: Discussionmentioning

confidence: 99%

Cation-independent Mannose 6-Phosphate Receptor

Bohnsack

Song

Olson

et al. 2009

Journal of Biological Chemistry

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The 300-kDa cation-independent mannose 6-phosphate receptor (CI-MPR), which contains multiple mannose 6-phosphate (Man-6-P) binding sites that map to domains 3, 5, and 9 within its 15-domain extracytoplasmic region, functions as an efficient carrier of Man-6-P-containing lysosomal enzymes. To determine the types of phosphorylated N-glycans recognized by each of the three carbohydrate binding sites of the CI-MPR, a phosphorylated glycan microarray was probed with truncated forms of the CI-MPR. Surface plasmon resonance analyses using lysosomal enzymes with defined N-glycans were performed to evaluate whether multiple domains are needed to form a stable, high affinity carbohydrate binding pocket. Like domain 3, adjacent domains increase the affinity of domain 5 for phosphomannosyl residues, with domain 5 exhibiting ϳ60-fold higher affinity for lysosomal enzymes containing the phosphodiester Man-P-GlcNAc when in the context of a construct encoding domains 5-9. In contrast, domain 9 does not require additional domains for high affinity binding. The three sites differ in their glycan specificity, with only domain 5 being capable of recognizing Man-P-GlcNAc. In addition, domain 9, unlike domains 1-3, interacts with Man 8 GlcNAc 2 and Man 9 GlcNAc 2 oligosaccharides containing a single phosphomonoester. Together, these data indicate that the assembly of three unique carbohydrate binding sites allows the CI-MPR to interact with the structurally diverse phosphorylated N-glycans it encounters on newly synthesized lysosomal enzymes.The 300-kDa cation-independent mannose 6-phosphate receptor (CI-MPR), 4 along with the smaller 46-kDa homodimeric cation-dependent mannose 6-phosphate receptor (CD-MPR), play an essential role in the degradative metabolism of cells by delivering ϳ60 different mannose 6-phosphate (Man-6-P)-tagged lysosomal enzymes from the secretory pathway to the endosomal/lysosomal system. Newly synthesized lysosomal enzymes are modified with phosphomannosyl residues on their N-glycans as they traverse the Golgi (1-3). In early Golgi compartments, UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc phosphotransferase; IUBMB accession number EC 2.7.8.17), adds N-acetylglucosamine (GlcNAc)-1-phosphate to the C-6 hydroxyl group of mannose residues to form a phosphodiester, Man-P-GlcNAc ( Fig. 1) (4 -7). The second enzyme, N-acetylglucosamine-1-phosphodiester ␣-N-acetylglucosaminidase (uncovering enzyme) (IUBMB accession number EC 3.1.4.45), removes the GlcNAc moiety in the trans Golgi network to generate a phosphomonoester ( Fig. 1) (8 -12). This recognition system is critical for normal development because a genetic defect in GlcNAc phosphotransferase causes the lysosomal storage disorders mucolipidosis II and III, with the more severe of these disorders, mucolipidosis II, resulting in death often within the first decade of life (13). The CI-MPR has been shown to be more efficient in targeting lysosomal enzymes to the lysosome than the CD-MPR, both in vitro (14, 15) and in vi...

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“…As mannose-6-phosphate (M6P) inhibits the activation of TGF-β1 and TGF-β2 [52, 53], local application of recombinant MP6 has been studied to treat scars (clinicalTrials.gov identifiers: NCT00984516 and NCT 00984854) by the pharmacological and biotech company Renovo, using the brand drug name Juvidex® [54]. In March 2009, Renovo reported the results of a double-blind, placebo-controlled, randomized, phase 2 efficacy trial in almost 200 male and female individuals with Juvidex® at different dosages in split-thickness skin-graft donor sites.…”

Section: Human Recombinant Tgf-β3 and Tgf-β Superfamily-related Prmentioning

confidence: 99%

New molecular medicine-based scar management strategies

Arno

Gauglitz

Barret

et al. 2014

Burns

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Keloids and hypertrophic scars are prevalent disabling conditions with still suboptimal treatments. Basic science and molecular-based medicine research has contributed to unravel new bench-to-bedside scar therapies, and to dissect the complex signaling pathways involved. Peptides such as transforming growth factor beta (TGF-β) superfamily, with SMADs, Ski, SnoN, Fussels, endoglin, DS-Sily, Cav-1p, AZX100, thymosin-β4 and other related molecules may emerge as targets to prevent and treat keloids and hypertrophic scars. The aim of this review is to describe the basic complexity of these new molecular scar management strategies, and point out new fibrosis research lines.

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Mannose 6-Phosphate Receptor Targeting and its Applications in Human Diseases

Cited by 160 publications

References 115 publications

Controlled Synthesis of End-Functionalized Mannose-6-phosphate Glycopolypeptides for Lysosome Targeting

Controlled Synthesis of End-Functionalized Mannose-6-phosphate Glycopolypeptides for Lysosome Targeting

Cation-independent Mannose 6-Phosphate Receptor

New molecular medicine-based scar management strategies

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