Different Distribution Patterns of the Two Mannose 6-phosphate Receptors in Rat Liver

Waguri, Satoshi; Kohmura, Mari; Kanamori, Shiro; Watanabe, Tsuyoshi; Ohsawa, Yoshiyuki; Koike, Masato; Tomiyama, Yoichiro; Wakasugi, Masaki; Kominami, Eiki; Uchiyama, Yasuo

doi:10.1177/002215540104901108

Cited by 19 publications

(10 citation statements)

References 52 publications

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“…This is in line with biochemical data showing a moderate but significant decrease of activity of lysosomal enzymes in several organs, but not in liver (Sohar et al, 1998). On the other hand, at least in rat liver CI-MPR has a significantly higher expression in hepatocytes than CD-MPR (Waguri et al, 2001). Moreover, a large increase of lysosomal enzymes in serum of CI-MPR-deficient mice points to mis-sorting of enzymes (Sohar et al, 1998).…”

Section: Discussionsupporting

confidence: 88%

Deficiency of mannose 6‐phosphate receptors and lysosomal storage: a morphometric analysis of hepatocytes of neonatal mice

Schellens

Säftig

Figura

et al. 2003

Cell Biology International

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Transport of lysosomal enzymes is mediated by two mannose 6-phosphate receptors: a cation dependent (CD-MPR) and a cation independent receptor (CI-MPR). In the present study the effect of MPR-deficiency on the lysosomal system of neonatal mouse hepatocytes was studied by ultrastructural morphometric analyses. The volume density of the lysosomal system in hepatocytes of mice that lack both receptors was significantly increased in comparison with controls and with mice deficient for CI-MPR only. This higher volume density was due to a nine-fold increase of residual bodies. In CI-MPR-deficient mice the volume density of the lysosomal system was not different from controls and no increase of residual bodies was observed. It is concluded that in hepatocytes of MPR-deficient neonatal mice lysosomal storage occurs when both MPRs are lacking, whereas deficiency of CI-MPR only has no effect on the ultrastructure of the lysosomal system.

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Section: Discussionsupporting

confidence: 88%

Deficiency of mannose 6‐phosphate receptors and lysosomal storage: a morphometric analysis of hepatocytes of neonatal mice

Schellens

Säftig

Figura

et al. 2003

Cell Biology International

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“…However, it should be pointed out that the acid hydrolases of the UCE Ϫ/Ϫ mice do not bind to the CD-MPR. It has been reported that although most cell types express both the CI-MPR and the CD-MPR, some cell types such as Kupffer cells, selectively express the CD-MPR (Waguri et al, 2001). Such cell types are candidates for hypersecretion of acid hydrolases in the UCE Ϫ/Ϫ mice plasma.…”

Section: Discussionmentioning

confidence: 99%

Mice Lacking Mannose 6-Phosphate Uncovering Enzyme Activity Have a Milder Phenotype than Mice Deficient forN-Acetylglucosamine-1-Phosphotransferase Activity

Boonen

Vogel

Platt

et al. 2009

MBoC

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The mannose 6-phosphate (Man-6-P) lysosomal targeting signal on acid hydrolases is synthesized by the sequential action of uridine 5-diphosphate-N-acetylglucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase) and GlcNAc-1-phosphodiester ␣-N-acetylglucosaminidase ("uncovering enzyme" or UCE). Mutations in the two genes that encode GlcNAc-1-phosphotransferase give rise to lysosomal storage diseases (mucolipidosis type II and III), whereas no pathological conditions have been associated with the loss of UCE activity. To analyze the consequences of UCE deficiency, the UCE gene was inactivated via insertional mutagenesis in mice. The UCE ؊/؊ mice were viable, grew normally and lacked detectable histologic abnormalities. However, the plasma levels of six acid hydrolases were elevated 1.6-to 5.4-fold over wild-type levels. These values underestimate the degree of hydrolase hypersecretion as these enzymes were rapidly cleared from the plasma by the mannose receptor. The secreted hydrolases contained GlcNAc-P-Man diesters, exhibited a decreased affinity for the cation-independent mannose 6-phosphate receptor and failed to bind to the cation-dependent mannose 6-phosphate receptor. These data demonstrate that UCE accounts for all the uncovering activity in the Golgi. We propose that in the absence of UCE, the weak binding of the acid hydrolases to the cation-independent mannose 6-phosphate receptor allows sufficient sorting to lysosomes to prevent the tissue abnormalities seen with GlcNAc-1-phosphotranferase deficiency.

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“…From these data, nonparenchymal liver cells are supposed to be susceptible for the mitogenic effects of IGFs through the presence of the IGF‐IR while hepatocytes have not been thought to be a major target for the actions of IGF‐I. In contrast to the IGF‐IR, expression of the IGF‐II/M6‐PR has been demonstrated in hepatocytes as well as in nonparenchymal liver cells including MF (Zindy et al, 1992; Schmitz et al, 1995; Scharf et al, 1997; Waguri et al, 2001). Since one of the major functions of IGF‐II/M6‐PR is to regulate extracellular levels of IGFs by mediating endocytosis and delivery of these growth factors to lysosomes for final degradation, both hepatocytes and nonparenchymal liver cells are not only the cellular source of IGF‐I, but are also capable to take up and degrade IGFs in the liver, thus providing an equilibrium of these growth factors under physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

Expression and regulation of the insulin‐like growth factor axis components in rat liver myofibroblasts

Novosyadlyy

Tron

Dudás

et al. 2004

Journal Cellular Physiology

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Apart from hepatic stellate cells (HSC), liver myofibroblasts (MF) represent a second mesenchymal cell population involved in hepatic fibrogenesis. The IGF system including the insulin‐like growth factors I and II (IGF‐I, ‐II), their receptors (IGF‐I receptor, IGF‐IR; IGF‐II/mannose 6‐phosphate receptor, IGF‐II/M6‐PR), and six high affinity IGF binding proteins (IGFBPs) participate in the regulation of growth and differentiation of cells of the fibroblast lineage, possibly contributing to the fibrogenic process. The aim of this work was to study the expression and regulation of the IGF axis components in rat liver MF. Methods: Cultures of MF from passages 1 to 4 (P1–4) were studied. IGFBP secretion was analyzed by [125I]‐IGF‐I ligand and immunoblotting. IGF‐I, IGF‐IR, IGF‐II/M6‐PR, and IGFBP messenger RNA (mRNA) expression was assessed by Northern blot hybridization. DNA synthesis was evaluated by 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation assay. Results: MF from P1 to 4 constitutively expressed mRNA transcripts specific for IGF‐I, IGF‐IR, and IGF‐II/M6‐PR. In MF, biosynthesis of IGFBP‐3 and ‐2 was observed that was stimulated by IGF‐I, insulin, and transforming growth factor β (TGF‐β), whereas platelet‐derived growth factor (PDGF‐BB) revealed inhibitory effects. IGF‐I and to a lesser extent insulin increased DNA synthesis of MF. Simultaneous addition of recombinant human IGFBP‐2 or ‐3 with IGF‐I diminished the mitogenic effect of IGF‐I on MF whereas preincubation of MF with IGFBP‐2 or ‐3 further potentiated the IGF‐I stimulated DNA synthesis. In conclusion, the present study demonstrates that the IGF axis may play a role in the regulation of MF proliferation in vitro which might be relevant in vivo for the process of fibrogenesis during acute and chronic liver injury. © 2004 Wiley‐Liss, Inc.

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Different Distribution Patterns of the Two Mannose 6-phosphate Receptors in Rat Liver

Cited by 19 publications

References 52 publications

Deficiency of mannose 6‐phosphate receptors and lysosomal storage: a morphometric analysis of hepatocytes of neonatal mice

Deficiency of mannose 6‐phosphate receptors and lysosomal storage: a morphometric analysis of hepatocytes of neonatal mice

Mice Lacking Mannose 6-Phosphate Uncovering Enzyme Activity Have a Milder Phenotype than Mice Deficient forN-Acetylglucosamine-1-Phosphotransferase Activity

Expression and regulation of the insulin‐like growth factor axis components in rat liver myofibroblasts

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