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Query: UNIPROT:P20645 (mannose-6-phosphate receptor)
 320 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin-like growth factor-II/mannose-6-phosphate receptor binds two classes of ligands, IGF-II and lysosomal enzymes containing the mannose-6-phosphate recognition marker. To study the interaction of the two classes of ligands at the receptor level, we have isolated 'high uptake' forms of lysosomal enzymes containing mannose-6-phosphate that had been radiolabeled biosynthetically using a tissue culture model: Tay-Sachs disease fibroblasts were incubated in medium containing [3H]mannose, ammonium chloride and mannose-6-phosphate. Under the conditions of these experiments, the Tay-Sachs disease fibroblasts synthesized and secreted radiolabeled hexosaminidase B, as confirmed by measuring enzymatic activity of cell-conditioned medium. The enzyme secreted was recognized by antibodies raised against purified hexosaminidase A and B but not by nonimmune control sera in Western blotting and immunoprecipitation experiments. The radiolabeled cell-conditioned medium was partially purified by ion-exchange chromatography on a DEAE-Sephadex column. When partially purified [3H]hexosaminidase B was incubated with rat C6 glial cells which express large numbers of IGF-II/mannose-6-phosphate receptors, the enzyme was taken up specifically via the IGF-II/mannose-6-phosphate receptor as evidenced by carbohydrate competition experiments. The specific uptake of the radiolabeled lysosomal enzyme was partially inhibited by IGF-II and an antibody against the IGF-II/mannose-6-phosphate receptor (No. 3637). We conclude that the cellular uptake of a biosynthetically labeled lysosomal enzyme, hexosaminidase B, is partially inhibited by IGF-II. We hypothesize that IGF-II might be capable of modulating lysosomal pathways in vivo.
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PMID:Biosynthetic labeling of beta-hexosaminidase B: inhibition of the cellular uptake of lysosomal secretions containing [3H]hexosaminidase B by insulin-like growth factor-II in rat C6 glial cells. 130 95

After 3 or 4 weeks of age, insulin-like growth factor-II (IGF-II) gene expression in normal rats has been detected only in mesenchymal tissue associated with the central nervous system. In contrast, the IGF-II/mannose-6-phosphate receptor has been reported to be widely distributed in adult rat brain. This study was performed in order to clarify the cellular localization of IGF-II and IGF-II/mannose-6-phosphate receptor in rat brain by comparing an immunocytochemical map with the distribution of mRNAs by in situ hybridization. The highest levels of IGF-II mRNA were detected in the choroid plexus and meningeal membranes. In contrast, IGF-II receptor transcripts were mainly present in neuron-rich areas such as the hippocampus, with a lower signal present in the choroid plexus and meninges. Specific IGF-II receptor immunoreactivity was present in neurons throughout the forebrain, with the highest intensity in the pyramidal cell and polymorphic layers of the hippocampus and the granule cell layer of the dentate gyrus. This distribution was similar to that obtained with the in situ hybridization technique. No glial staining was detected. Although the role of IGF-II in the adult rat brain, acting through its specific receptor, is not clear; in vitro and in vivo data suggest a possible neurotropic and/or neuromodulatory action.
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PMID:Expression of insulin-like growth factor-II (IGF-II) and IGF-II/mannose-6-phosphate receptor in the rat hippocampus: an in situ hybridization and immunocytochemical study. 139 8

Recent studies have established that in mammalian cells insulin-like growth factor-II can couple the large mannose-6-phosphate receptor to a GTP-binding protein and that the insulin-like growth factor-II-induced activation of the GTP-binding protein is inhibited by mannose-6-phosphate and lysosomal enzymes. In mouse, the gene for the large mannose-6-phosphate receptor is maternally imprinted.
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PMID:Molecular recognition and targeting of lysosomal proteins. 166 72

Some peptide hormones are associated with specific, high-affinity plasma proteins. The major binding protein (BP) for growth hormone (GH) in humans is a circulating fragment of the GH membrane receptor, consisting of the hydrophilic, extracellular portion of that transmembrane glycoprotein. The circulating levels of GH-BP mirror the levels of GH receptors. There are 4 well-characterized insulin-like growth factor (IGF)-BPs. One IGF-binding component in plasma is a fragment of the extracellular portion of the IGF-II/mannose-6-phosphate receptor, analogous to the GH-BP. The 3 other cloned IGF-BPs form a homologous family of proteins with differences in structure, glycosylation and hormonal control that suggest differences in function. The GH- and IGF-BPs play a major role in the metabolism and biological action of these peptide hormones.
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PMID:Role of growth-hormone and insulin-like growth-factor-binding proteins. 169 1

The intraovarian insulin-like growth factor (IGF) system constitutes a triad composed of ligands, receptors, and binding proteins. Although conventional radioligand receptor assays have documented the presence of specific receptors for insulin and insulin-like peptides in some rat somatic ovarian cell types, the exact cellular localization and hormonal regulation of the receptors in question remain matters of inquiry. To reevaluate the very presence, cellular localization, and hormonal regulation of the IGF receptor gene family in the rat ovary, solution hybridization/RNase protection assays were used wherein ovarian total RNA (20 micrograms) from immature (21-23 days old) rats was hybridized with 32P-labeled type I IGF receptor, type II IGF/mannose-6-phosphate receptor, and insulin receptor riboprobes. Single protected fragments 261 (type I IGF receptor), 500 (type II IGF/mannose-6-phosphate receptor), and 478 (insulin receptor) bases long were evident in whole ovary, granulosa, and theca-interstitial cells. Hypophysectomy of immature rats led to significant (P less than 0.05) albeit variable decrements in the relative (densitometrically quantified) ovarian abundance of transcripts corresponding to the type I IGF (but not insulin or type II IGF/mannose-6-phosphate) receptor. Treatment of immature hypophysectomized rats with FSH (10 micrograms/rat.day x 2.5 days) resulted in a significant (P less than 0.05) increase (4-fold) in transcripts corresponding to the type I IGF receptor in both whole ovarian material and freshly isolated granulosa cells. Similar (3.7-fold) increments (P less than 0.05) were noted after treatment with a diethylstilbestrol-containing sc silastic implant applied for a total of 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin-like growth factor receptor gene expression in the rat ovary: divergent regulation of distinct receptor species. 172 86

Endogenous and exogenous phosphomannosyl ligands inhibit binding of insulin-like growth factor-II (IGF-II) to the IGF-II/mannose-6-phosphate receptor (IGF-II/Man-6-P receptor). In the present study, the mechanism of this antagonism was examined using a [125I]IGF-II cross-linking assay with disuccinimidyl suberate in cell membranes. Treatment with 5 mM Man-6-P enhanced [125I]IGF-II cross-linking to the receptor. The magnitude of the Man-6-P enhancement differed depending on the source of the membranes, ranging from a 30% increase in JEG-3 human choriocarcinoma up to a 560% increase in B16-F1 mouse melanoma. Man-6-P stimulated [125I]IGF-II-receptor cross-linking in H-35 hepatoma membranes by about 80%, even at concentrations of labeled IGF-II (greater than or equal to 10 nM) that nearly saturated the receptors. Thus, in addition to its effect on IGF-II-binding affinity, Man-6-P caused a 1.5- to 2-fold increase in cross-linking efficiency within the IGF-II-receptor complex. Furthermore, Man-6-P enhanced [125I]IGF-II cross-linking to the H-35 receptor by a constant (approximately 80%) increment 1) when the cross-linking reaction was conducted in buffers of different pH over the range 6.8-8.0, or 2) using cross-linking agents differing in spacer arm length from 6.4-16.1 A. Washing membranes before assay with either Man-6-P (pH 7.4) or 0.5 M NaCl (pH 4.5) reduced the subsequent Man-6-P enhancement of [125I]IGF-II-receptor cross-linking, suggesting that this phenomenon was actually due to displacement of inhibitory phosphomannosyl ligands bound endogenously to the Man-6-P sites of the receptor. In support of this hypothesis, Man-6-P produced a minimal (8-14%) enhancement of [125I]IGF-II-receptor cross-linking in membranes from I-cell fibroblasts lacking such phosphomannosyl ligands. Thus, phosphomannosyl ligands bound to the IGF-II/Man-6-P receptor decrease both IGF-II-binding affinity and IGF-II-receptor cross-linking efficiency. Membrane-associated receptors appear to exist in experimentally and perhaps functionally distinct populations, depending on occupancy of the Man-6-P-binding sites.
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PMID:Mannose-6-phosphate enhances cross-linking efficiency between insulin-like growth factor-II (IGF-II) and IGF-II/mannose-6-phosphate receptors in membranes. 184 7

Diabetic renal hypertrophy is preceded by a transient increase in kidney insulin-like growth factor I and insulin-like growth factor binding protein concentration suggesting a renotropic function in diabetic kidney growth. In order to further examine the possible involvement of the insulin-like growth factor system in initial diabetic kidney growth, we have studied the expression of the kidney insulin-like growth factor II/mannose-6-phosphate receptor during the first 4 days after induction of diabetes in rats. Using a specific antiserum (#3637) raised against the insulin-like growth factor II/mannose-6-phosphate receptor of rat chondrosarcoma a specific band with an apparent molecular weight of 220 kDa was identified in Western blotting experiments with kidney and liver protein extracts. In untreated diabetic rats a transient increase of the kidney and liver insulin-like growth factor II/mannose-6-phosphate receptor concentration was measured 24-48 h after the induction of diabetes (mean increase in kidney 140% and liver 112%, n = 5). This increase was followed by a subsequent decrease in the insulin-like growth factor II/mannose-6-phosphate receptor protein concentration after 3-4 days of diabetes. Insulin treatment prevented the rise both in kidney and liver tissue. Kidney weight in untreated diabetic rats increased by 25% after 4 days. In conclusion, the present study shows a transient increase of insulin-like growth factor II/mannose-6-phosphate receptor concentration in hypertrophying diabetic kidneys and in diabetic livers, contemporarily with the previously described increase in kidney insulin-like growth factor I and insulin-like growth factor binding protein content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased kidney and liver insulin-like growth factor II/mannose-6-phosphate receptor concentration in experimental diabetes in rats. 775 75

Insulin-like growth factor II (IGF-II) has been implicated in the differentiation of skeletal muscle cells. In this study the putative role of IGF-II in epithelial cell differentiation was investigated. The expression of IGF-II, IGF-I receptor and IGF-II/mannose-6-phosphate receptor (IGF-II/M6P receptor) mRNA during spontaneous differentiation of the colon carcinoma cell line Caco-2 was measured. In addition, differentiation of Caco-2 cells during the cell culture period (days 1-21 in culture) was studied in parallel using morphological (light and scanning electron microscopy) and biochemical markers of growth (DNA, RNA and protein content, and beta-actin mRNA and glyceraldehyde phosphate dehydrogenase mRNA expression) and differentiation (alkaline phosphatase activity, carcinoembryonic antigen content). A putative correlation between the markers of growth and differentiation and IGF gene expression was studied using linear regression analysis. Expression of IGF-II mRNA and IGF-II/M6P receptor mRNA correlated significantly with the progress of differentiation, while the IGF-I receptor was stably expressed throughout the culture period and exhibited a crucial role for the survival of Caco-2 cells, as shown by blocking experiments employing the monoclonal anti-IGF-I receptor antibody alpha-IR3. We hypothesize that: IGF-II mRNA and IGF-II/M6P receptor mRNA are expressed in a coordinate fashion during the differentiation of Caco-2 cells; coordinate expression of IGF-II and of IGF-II/M6P receptor mRNA might point to a role for IGF-II as a growth stimulant and for the IGF-II/M6P receptor for a regulator of IGF-II bioavailability in differentiating cells; alternatively, high IGF-II/M6P receptor mRNA and protein expression in differentiated cells but low IGF-II binding to the IGF-II/M6P receptor point to an important intracellular role of this receptor type in differentiated colon epithelial cells; the IGF-I receptor mRNA is stably expressed during the differentiation process of Caco-2 cells; the IGF-I receptor protein seems to be a prerequisite for the survival of Caco-2 cells.
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PMID:Coordinate expression of insulin-like growth factor II (IGF-II) and IGF-II/mannose-6-phosphate receptor mRNA and stable expression of IGF-I receptor mRNA during differentiation of human colon carcinoma cells (Caco-2). 876 74

The pharmacological characteristics, localization and process of internalization of the insulin-like growth factor I and II receptors were studied in rat primary hippocampal cultured neurons grown under serum-free conditions. [125I]insulin-like growth factor-I binding was specific with an apparent affinity (Kd) of 0.1 nM and IC50 values of 0.1, 2.9 and 99.7 nM for insulin-like growth factor-I, insulin-like growth factor-II and insulin, respectively. The competition by insulin suggests the presence of genuine insulin-like growth factor-I receptors and not insulin-like growth factor binding proteins. In contrast, [125I]insulin-like growth factor-II binding showed a Kd of 0.1 nM and IC50 values of 0.2 and 20.5 nM for insulin-like growth factor-II and insulin-like growth factor-I while insulin was inactive, a well established characteristic of the insulin-like growth factor-II receptor. Using emulsion autoradiography, specific binding sites for [125I]insulin-like growth factor-I and -II were over the whole cultured neurons. The use of selective insulin-like growth factor-I and -II receptor antibodies further confirmed the existence of these receptors in rat hippocampal cultured neurons. To investigate the respective internalization profile of [125I]insulin-like growth factor-I and [125I]insulin-like growth factor-II receptor-ligand complexes in neurons, a technique of acid stripping was used. The apparent rate of endocytosis was found to be greater for the insulin-like growth factor-II than for the insulin-like growth factor-I receptor complexes. The internalization of [125I]insulin-like growth factor-I and [125I]insulin-like growth factor-II ligand-receptor complexes was confirmed using phenylarsine oxide which significantly blocked both internalization processes. In order to eliminate possible receptor recycling, monensin was used and shown to have no effect on the internalization of either ligand. Since the insulin-like growth factor-I receptor is coupled to tyrosine kinase activity, tyrphostin 47, a specific tyrosine kinase inhibitor. was used and shown to decrease [125I]insulin-like growth factor-I but not the [125I]insulin-like growth factor-II receptor internalization profile. Accordingly, insulin-like growth factor-I is apparently internalized mostly via the insulin-like growth factor-I tyrosine kinase type receptor, while insulin-like growth factor-II is not. The insulin-like growth factor-II receptor ligand complex is likely internalized via a pathway possibly related to mannose-phosphorylated residues as the insulin-like growth factor-II/mannose-6-phosphate receptor has been implicated in the intracellular targeting of lysosomal proteins containing glycosylated residues. Taken together, our results indicate that primary hippocampal cultured neurons represent a unique model for investigating the differential role and intracellular trafficking of both insulin-like growth factor-I and insulin-like growth factor-II receptor ligand complexes and their relevance to the respective functional role of these two-related trophic factors in the central nervous system.
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PMID:Presence and differential internalization of two distinct insulin-like growth factor receptors in rat hippocampal neurons. 914 94

The insulin-like growth factor-II (IGF-II) receptor (IGF-IIR) is a single-chain transmembrane protein identical to the mannose-6-phosphate receptor. In the present study we examined IGF-IIR expression in normal and cancerous human pancreatic tissues. In the normal pancreas, moderately strong IGF-IIR immunoreactivity was present in the cytoplasm of islet cells, and mild cytoplasmic immunoreactivity was evident occasionally in ductal and acinar cells. Some ductal cells also exhibited nuclear IGF-IIR immunoreactivity. In the pancreatic cancers, regions of strong IGF-IIR immunoreactivity were present in the duct-like cancer cells within the tumor mass, often exhibiting nuclear localization. Expression of IGF-IIR mRNA in the cancer cells was confirmed by in situ hybridization. By comparison with normal pancreatic tissues, 7 of 12 pancreatic cancers exhibited a 5.6-fold increase in IGF-IIR mRNA levels, whereas in 3 cancers the IGF-IIR transcript was below the level of detection. Furthermore, all six tested cultured human pancreatic cancer cell lines expressed the IGF-IIR mRNA transcript. Our data indicate that IGF-IIR is overexpressed in a significant number of human pancreatic cancers, where it has a tendency to localize in the nucleus, and raise the possibility that IGF-IIR may contribute to the pathobiology of pancreatic cancer.
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PMID:Altered expression of insulin-like growth factor II receptor in human pancreatic cancer. 936 Oct 90


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