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)

Intracisternal granules (ICGs) are insoluble aggregates of pancreatic digestive enzymes and proenzymes that develop within the lumen of the rough endoplasmic reticulum of exocrine pancreatic cells, especially in guinea pigs. These ICGs are eliminated by autophagy. By morphological criteria, we identified three distinct and sequential classes of autophagic compartments, which we refer to as phagophores, Type I autophagic vacuoles, and Type II autophagic vacuoles. Lobules of guinea pig pancreas were incubated in media containing HRP for periods of 5-120 min to determine the relationship between the endocytic and autophagic pathways. Incubations with HRP of 15 min or less labeled early endosomes at the cell periphery that were not involved in autophagy of ICGs, but after these short incubations none of the autophagic compartments were HRP positive. After 30-min incubation with HRP, early endosomes at the cell periphery, late endosomes in the pericentriolar region, and, in addition, Type I autophagic vacuoles containing ICGs were all labeled by the tracer. Type II autophagic vacuoles were not labeled after 30-min incubation with HRP but were labeled after incubations of 60-120 min. Phagophores did not receive HRP even after 120 min incubations. We concluded that the autophagic and endocytic pathways converge immediately after the early endosome level and that Type I autophagic vacuoles precede Type II autophagic vacuoles on the endocytic pathway. We studied the distribution of acid phosphatase, lysosomal proteases and cation-independent-mannose-6-phosphate receptor (CI-M6PR) in the three classes of autophagic compartments by histochemical and immunocytochemical methods. Phagophores, the earliest autophagic compartment, contained none of these markers. Type I autophagic vacuoles contained acid phosphatase but, at most, only very low levels of cathepsin D and CI-M6PR. Type II autophagic vacuoles, by contrast, are enriched for acid phosphatase, cathepsin D, and other lysosomal enzymes, and they are also enriched for CI-M6PR. Moreover, soluble fragments of bovine CI-M6PR conjugated to colloidal gold particles heavily labeled Type II but not Type I autophagic vacuoles, and this labeling was specifically blocked by mannose-6-phosphate. This indicates that the lysosomal enzymes present in Type II autophagic vacuoles carry mannose-6-phosphate monoester residues. Using 3-C2, 4-dinitroanilino-3'-amino-N-methyldipropylamine (DAMP), we showed that Type II autophagic vacuoles are acidic. We interpret these findings as indicating that Type II autophagic vacuoles are a prelysosomal compartment in which the already combined endocytic and autophagic pathways meet the delivery pathway of lysosomal enzymes.
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PMID:In exocrine pancreas, the basolateral endocytic pathway converges with the autophagic pathway immediately after the early endosome. 216 50

Cytolytic lymphocytes contain specialized lytic granules whose secretion during cell-mediated cytolysis results in target cell death. Using serial section EM of RNK-16, a natural killer cell line, we show that there are structurally distinct types of granules. Each type is composed of varying proportions of a dense core domain and a multivesicular cortical domain. The dense core domains contain secretory proteins thought to play a role in cytolysis, including cytolysin and chondroitin sulfate proteoglycan. In contrast, the multivesicular domains contain lysosomal proteins, including acid phosphatase, alpha-glucosidase, cathepsin D, and LGP-120. In addition to their protein content, the lytic granules have other properties in common with lysosomes. The multivesicular regions of the granules have an acidic pH, comparable to that of endosomes and lysosomes. The granules take up exogenous cationized ferritin with lysosome-like kinetics, and this uptake is blocked by weak bases and low temperature. The multivesicular domains of the granules are rich in the 270-kD mannose-6-phosphate receptor, a marker which is absent from mature lysosomes but present in earlier endocytic compartments. Thus, the natural killer granules represent an unusual dual-function organelle, where a regulated secretory compartment, the dense core, is contained within a pre-lysosomal compartment, the multivesicular domain.
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PMID:The lytic granules of natural killer cells are dual-function organelles combining secretory and pre-lysosomal compartments. 227 62

Human lysosomal acid phosphatase is transported as a transmembrane protein to lysosomes, where it is converted into a soluble protein by a limited proteolysis (Waheed et al., 1988, EMBO J. 7, 2351-2358). Transport of human lysosomal acid phosphatase in heterologous BHK-21 cells was examined under conditions that impair mannose-6-phosphate receptor-dependent transport, N-glycosylation or processing of N-linked oligosaccharides. Targeting of lysosomal acid phosphatase to lysosomes was neither affected by antibodies blocking the mannose-6-phosphate/IGF II receptor, nor by NH4Cl, which inhibited the mannose-6-phosphate receptor-dependent targeting of soluble lysosomal enzymes. 1-Deoxynojirimycin, 1-deoxymannojirimycin and swainsonine inhibited processing of N-linked oligosaccharides in lysosomal acid phosphatase without significantly affecting its transport. Tunicamycin inhibited N-glycosylation of lysosomal acid phosphatase. The non-glycosylated lysosomal acid phosphatase polypeptides accumulated within light membranes and were not transported to dense lysosomes. These results indicate that transport of lysosomal acid phosphatase is independent of mannose-6-phosphate receptors, does not involve an acid pH-dependent step and does not require processing of N-linked oligosaccharides. N-glycosylation appears to be necessary to achieve a transport competent form of lysosomal acid phosphatase.
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PMID:Targeting of lysosomal acid phosphatase with altered carbohydrate. 254 Jul 67

Electron microscopic approaches have been used to study the endocytic pathways from the apical and basolateral surface domains of the polarized epithelial cell, MDCK strain I, grown on polycarbonate filters. The cells were incubated at 37 degrees C in the presence of two distinguishable markers administered separately to the apical or the basolateral domain. Initially each marker was visualized within distinct apical or basolateral peripheral endosomes. However, after 15 min at 37 degrees C, both markers were observed within common perinuclear structures. The compartment in which meeting first occurred was shown to be a late endosome (prelysosome) that labeled extensively with antibodies against the cation-independent mannose-6-phosphate receptor (MPR) on cryosections. With increasing incubation times, markers passed from these MPR-positive structures into a common set of MPR-negative lysosomes that were mainly located in the apical half of the cell. A detailed quantitative analysis of the endocytic pathways was carried out using stereological techniques in conjunction with horseradish peroxidase and acid phosphatase cytochemistry. This enabled us to estimate the absolute volumes and membrane surface areas of the endocytic organelles involved in apical and basolateral endocytosis.
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PMID:Meeting of the apical and basolateral endocytic pathways of the Madin-Darby canine kidney cell in late endosomes. 255 51

The intracellular and extracellular distribution of acid hydrolases in cultured retinal pigmented epithelium (RPE) was studied. Incubation of cultured RPE in medium containing 20 mM mannose-6-phosphate resulted in the extracellular release of approximately 15% of the cell-associated activity of several acid hydrolases. This represents an approximate 120% increase over control levels after 24 hr of culture with 20 mM mannose-6-phosphate. The extracellular release is not due to cell lysis, since no release of the cytoplasmic marker lactate dehydrogenase was seen. n-Acetyl-beta-glucosaminidase, alpha-mannosidase, and beta-glucuronidase were released into the extracellular medium, while acid phosphatase and beta-glucosidase were not. The release was specific for mannose-6-phosphate, and was dose-dependent. Inhibition of protein synthesis by treatment of RPE cells with cycloheximide (100 micrograms/ml) inhibited extracellular acid hydrolase release. RPE cells exhibited n-Acetyl-beta-glucosaminidase bound to the cell surface via a mannose-6-phosphate sensitive receptor. These results demonstrate a specific extracellular release of acid hydrolases by RPE and the presence of at least one acid hydrolase on the RPE cell surface. This may represent a mechanism for control of cell surface and extracellular levels of these enzymes in RPE via the mannose-6-phosphate receptor.
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PMID:Extracellular release of acid hydrolases from cultured retinal pigmented epithelium. 310 Apr 74