Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20645 (mannose-6-phosphate receptor)
 320 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Solution hybridization/RNase protection assays were used to study the developmental expression of the insulin-like growth factor-I (IGF-I), IGF-II, IGF-I receptor, and IGF-II/mannose-6-phosphate receptor genes in the rat ovary between postnatal days 1-80. Maximal IGF-I mRNA levels occurred during the 15- to 25-day postnatal period, and the level on day 20 represented a 9-fold increase over the baseline at earlier and later stages. IGF-II mRNA levels were maximal during the 1- to 5-day postnatal period and subsequently declined to undetectable levels after day 10. IGF-I receptor mRNA levels increased 10-fold to a maximum in the 20- to 25-day postnatal period. This pattern was similar to the developmental pattern of [125I]IGF-I binding in the ovary. Two apparent peaks of IGF-II/mannose-6-phosphate receptor mRNA levels were seen, on day 20 and between days 50-80. These specific and significant changes in the expression of the genes encoding the IGFs and their receptors suggest a role for the IGF system in postnatal ovarian development.
Endocrinology 1992 Sep
PMID:Expression of the insulin-like growth factor (IGF)-I and -II and the IGF-I and -II receptor genes during postnatal development of the rat ovary. 132 54

MARCKS is a specific protein kinase C (PKC) substrate that binds both calmodulin and actin and is phosphorylated during phagocyte activation, neurosecretion, and growth factor-dependent mitogenesis. We report here on MacMARCKS, a MARCKS homolog, whose synthesis is dramatically increased in macrophages when these cells are exposed to bacterial lipopolysaccharide. We have purified rabbit MacMARCKS and cloned its cDNA from rabbit and mouse. The effector domains of MacMARCKS and MARCKS are nearly identical, and both proteins bind calmodulin in a phosphorylation-regulated manner. MacMARCKS and MARCKS also share a second, highly conserved region also found in the internalization domain of the mannose-6-phosphate receptor. Our data suggest the existence of a family of PKC substrates that are targeted to different subcellular locations and that function to integrate PKC and calcium/calmodulin-dependent signals in the control of the plastic actin cytoskeleton.
Cell 1992 Sep 04
PMID:MacMARCKS, a novel member of the MARCKS family of protein kinase C substrates. 151 35

The mouse insulin-like growth factor II (IGF-II) gene encodes a polypeptide that plays a role in embryonic growth. We have examined the temporal and spatial pattern of expression of this gene in sections of the mouse conceptus between embryonic days 4.0 and 8.5 by in situ hybridization. Abundant IGF-II transcripts were detected in all the trophectodermal derivatives, after implantation. Labeling was then observed in primitive endoderm, but was transient and disappeared after formation of the yolk sac. Expression was next detected in extraembryonic mesoderm at the early primitive streak stage. Labeling in the embryo proper appeared first at the late primitive streak/neural plate stage in lateral mesoderm and in anterior-proximal cells located between the visceral endoderm and the most cranial region of the embryonic ectoderm. The position of the latter cells suggests that their descendants are likely to participate in the formation of the heart and the epithelium of the ventral and lateral walls of the foregut, where intense labeling was observed at the neural fold stage. Hybridization was also detected in cranial mesenchyme, including neural crest cells. The intensity of hybridization signal increased progressively in paraxial (presomitic and somitic) mesoderm, while declining in the ectoplacental cone. The neuroectoderm and surface ectoderm did not exhibit hybridization at any stage. Immunohistochemical analysis indicated co-localization of IGF-II transcripts, translated pre-pro-IGF-II, and the cognate IGF-II/mannose-6-phosphate receptor. These correlations are consistent with the hypothesis that IGF-II has an autocrine function.
Development 1990 Sep
PMID:Pattern of the insulin-like growth factor II gene expression during early mouse embryogenesis. 196 8

Five healthy related individuals in 3 generations of a Lebanese family have been found to have highly elevated plasma lysosomal enzyme levels inherited as a dominant Mendelian trait. The same enzymes in other extracellular fluids were within normal limits. While the pattern and extent of plasma enzyme elevation was similar to that found in mucolipidoses II and III, the physicochemical properties of the elevated enzymes were different from those of both control and I-cell disease plasma. Secretion of lysosomal hydrolases into cell media by fibroblasts from one of the individuals was increased two to seven times more than that from controls. The results suggest faulty recognition between lysosomal hydrolases and mannose-6-phosphate receptors. This could be caused by a defect either in the phosphodiesterase that normally uncovers mannose-6-phosphate hydrolase markers or in the mannose-6-phosphate receptor itself.
Am J Hum Genet 1984 Sep
PMID:Five related Lebanese individuals with high plasma lysosomal hydrolases: a new defect in mannose-6-phosphate receptor recognition? 623 28

In vitro human natural cell-mediated cytotoxicity (NCMC) to K-562, Molt-4, and F-265 cells is inhibited in a dose-dependent manner by mannose 6-phosphate, fructose 1-phosphate and fructose 6-phosphate. This inhibition is not observed with mannose, glucose, fucose, glucose 6-phosphate, mannose 1-phosphate, galactose 1-phosphate, or galactose 6-phosphate. Preincubation of the effector cells, obtained from fresh whole blood, with mannose-6-phosphate, fructose-1-phosphate, or fructose-6-phosphate did not inhibit cytotoxicity, which indicated that these hexose phosphates are not nonspecifically toxic towards the effector lymphocytes. Mannose-6-phosphate and the stereochemically similar fructose-1-phosphate are more potent inhibitors than fructose-6-phosphate in terms of concentration required and time of onset of effect. Inhibition of cytotoxicity by mannose-6-phosphate varied with target cell type: F-265 is protected at much lower concentrations of mannose-6-phosphate (less than 1 mM) than is either Molt-4 or K-562. The inhibition of NCMC is also observed with the inhibitors of lysosomal function, NH4Cl, and chloroquine. The presence of a functional mannose-6-phosphate receptor on target cells was demonstrated: (i) Gelonin, a seed protein that inactivates the eukaryotic ribosome but is nontoxic to intact cells, was covalently linked to monophosphopentamannose, and this conjugate ws toxic to both K-562 and F-265 target cells, the latter being by far the more sensitive; and (ii) chloroquine, NH4Cl, and mannose-6-phosphate all inhibited the toxicity of gelonin-monophosphopentamannose. These results suggest either that a cytolytic lymphokine contains a hexose phosphate residue and may be taken up by target cells through the lysosomal/mannose 6-phosphate pathway or that such a residue is involved in target cell-effector cell recognition.
Proc Natl Acad Sci U S A 1981 Sep
PMID:Mannose 6-, fructose 1-, and fructose 6-phosphates inhibit human natural cell-mediated cytotoxicity. 694 16

Osteoclasts develop from precursor cells of the monocyte series. However, specialized differentiation for efficient bone degradation separates the osteoclast from the macrophage. The physical reasons for these differences are emerging from the study of osteoclastic physiology and biochemistry. Key osteoclast specializations are multinucleation, formation of a tightly sealed extracellular compartment on bone, and high-capacity secretion of HCl and acid proteases into this extracellular site. Multinucleation increases efficiency of extracellular attachment processes. The attachment process is mediated by cell membrane integrins, and is sensitive to changes in intracellular or extracellular calcium. Acid production exploits carbonic acid as the source of acid and conjugate base equivalents, reflected in abundant osteoclastic carbonic anhydrase type II expression. Secretion of acid involves extremely high expression of vacuolar-type H(+)-ATPase and a chloride channel in the cell's specialized acid secreting organelle, the ruffled membrane, which is polarized to the osteoclast's bone attachment. Acid secretion is balanced by chloride-bicarbonate exchange in the cell's nonbone attached membranes; this functionally resembles the band 3 chloride-bicarbonate exchanger of the red cell carbon dioxide transport system. Bone collagen is degraded by acid proteases secreted into the acid degradation site via the mannose-6-phosphate receptor system, which is targeted to lysosomes in other cells. Functional deficits, as in osteopetrosis, may affect any of the elements involved in osteoclast differentiation. Furthermore, new antiosteoclastic therapeutic agents may inhibit osteoclast biochemistry intentionally, such as for the control of hypercalcemia of malignancy.
Clin Orthop Relat Res 1993 Sep
PMID:Recent advances toward understanding osteoclast physiology. 839 72

Palmitoyl-protein thioesterase is a lysosomal long-chain fatty acyl hydrolase that removes fatty acyl groups from modified cysteine residues in proteins. Mutations in palmitoyl-protein thioesterase were recently found to cause the neurodegenerative disorder infantile neuronal ceroid lipofuscinosis, a disease characterized by accumulation of amorphous granular deposits in cortical neurons, leading to blindness, seizures, and brain death by the age of three. In the current study, we demonstrate that [35S]cysteine-labeled lipid thioesters accumulate in immortalized lymphoblasts of patients with infantile neuronal ceroid lipofuscinosis. The accumulation in cultured cells is reversed by the addition of recombinant palmitoyl-protein thioesterase that is competent for lysosomal uptake through the mannose-6-phosphate receptor. The [35S]cysteine-labeled lipids are substrates for palmitoyl-protein thioesterase in vitro, and their formation requires prior protein synthesis. These data support a role for palmitoyl-protein thioesterase in the lysosomal degradation of S-acylated proteins and define a major new pathway for the catabolism of acylated proteins in the lysosome.
Proc Natl Acad Sci U S A 1996 Sep 17
PMID:Lipid thioesters derived from acylated proteins accumulate in infantile neuronal ceroid lipofuscinosis: correction of the defect in lymphoblasts by recombinant palmitoyl-protein thioesterase. 881 48

Using the human macrophage hybridoma cell line 43 and primary monocytes, we investigated the regulation of class II expression and intracellular Ag trafficking after HIV-1 infection. The HIV-1-infected human macrophage hybridoma cell line, 43HIV, lost class II Ag expression, as determined by immunofluorescence, immunoprecipitation, and Northern blot analysis, 2 wk after infection. Class II expression could be restored by transfection with the full-length HLA-DR4 cDNA driven by a CMV IE promotor. However, even after transfection, the 43HIV cells were incapable of presenting Ag to MHC-matched Ag-specific T cells. This defect was associated with decreased formation of class II-Ag complexes, and similar findings were observed in primary HIV-1BaL-infected monocytes. We investigated Ag uptake using FITC-labeled tetanus, OVA, and keyhole limpet hemocyanin. There was decreased uptake of all three Ags after HIV-1 infection at different time points after Ag pulsing in the 43HIV cells and in primary HIV-1BaL-infected monocytes. There was colocalization of the FITC-labeled Ags with early (cathepsin D) and late endosomal markers (anti-mannose-6-phosphate receptor), lysosomal markers (CD-63), and acidic compartment markers (3-(2,4-dinitroanilino)-3'-amino-N-methyldipropylamine) in the uninfected cells, but the level of colocalized Ag was reduced in the 43HIV cells and HIV-1BaL-infected monocytes. Our data suggest that class II expression, formation of class II-Ag complexes, and Ag uptake are impaired in chronically HIV-1-infected monocytic cells, which may contribute to the global immunosuppression observed in AIDS.
J Immunol 1997 Sep 01
PMID:Impaired class II expression and antigen uptake in monocytic cells after HIV-1 infection. 927 5

The cytoplasmic tail of the human 46 kDa mannose 6-phosphate receptor (MPR 46) is necessary for rapid internalization of the receptor and sufficient to mediate internalization of a resident plasma membrane protein. To localize the internalization sequences within the 67 amino acids of the cytoplasmic tail, the tail was progressively shortened from its C-terminus, internal deletions of between four and eight amino acids were introduced into the tail, and individual residues were substituted by alanine, glycine or serine. Three sequences were identified that contribute to the internalization of MPR 46. The first is located within the 23 juxtamembrane cytoplasmic residues of the tail. It contains four essential residues within a heptapeptide and does not resemble known internalization signals. The second sequence contains as a critical residue Tyr-45. The third region is located within the C-terminal seven residues and contains a di-leucine pair as essential residues. The first and third sequences were shown to function as autonomous internalization sequences. Substitution of critically important residues within a single internalization sequence was tolerated, with no or only a moderate decrease in the internalization rate. When essential residues from two or all three internalization sequences were substituted, however, the internalization rate was decreased by more than 60% and 90% respectively. This indicates that the autonomous internalization signals in the cytoplasmic tail of MPR 46 function in an additive manner, but are partly redundant.
Biochem J 1997 Sep 01
PMID:Identification of three internalization sequences in the cytoplasmic tail of the 46 kDa mannose 6-phosphate receptor. 929 Nov 24

Myoblasts have properties that make them suitable vehicles for gene replacement therapy, and lysosomal storage diseases are attractive targets for such therapy. Type II Glycogen Storage Disease, a deficiency of acid alpha-glucosidase (GAA), results in the abnormal accumulation of glycogen in skeletal and cardiac muscle lysosomes. The varied manifestations of the enzyme deficiency in affected patient are ultimately lethal. We used a retroviral vector carrying the cDNA encoding for GAA to replace the enzyme in deficient myoblasts and fibroblasts and analyzed the properties of the transduced cells. The transferred gene was efficiently expressed, and the de novo-synthesized enzyme reached lysosomes where it digested glycogen. In enzyme-deficient myoblasts after transduction, enzyme activity rose to more than 30-fold higher than in normal myoblasts and increased about five-fold more when the cells were allowed to differentiate into myotubes. The transduced cells secreted GAA that was endocytosed via the mannose-6-phosphate receptor into lysosomes of deficient cells and digested glycogen. Moreover, the transduced myoblasts were able to fuse with and provide enzyme for GAA-deficient fusion partners. Thus, the gene-corrected cells, which appear otherwise normal, may ultimately provide phenotypic correction to neighboring GAA-deficient cells by fusion and to distant cells by secretion and uptake mechanisms.
Hum Gene Ther 1997 Sep 01
PMID:Retroviral transfer of acid alpha-glucosidase cDNA to enzyme-deficient myoblasts results in phenotypic spread of the genotypic correction by both secretion and fusion. 932 88


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