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)

Epithelial cells in situ can internalize their desmosomes. This can be induced in cell cultures after removal of calcium ions from the cell medium. To study this endocytic process, a nontumorigenic human breast epithelial cell line, HMT-3522, was used. HMT-3522 cells were grown in serum-free, chemically defined medium, containing epidermal growth factor (EGF). Removal of EGF from the medium led to growth arrest and a kind of epithelial differentiation process in which adjacent cells interdigitated and formed more desmosomes than in the proliferating state. Growth-inhibited HMT-3522 cells dissociated following EGTA treatment, the desmosomes divided in a symmetrical fashion, and the desmosomal plaques (half-desmosomes) on the cell surface became internalized. The internalization was independent of clathrin, since immunogold labeling of ultracryosections never showed clathrin on desmosomal plaque-associated membrane domains. Moreover, cytosol acidification, which selectively inhibits endocytosis from clathrin-coated pits, practically blocked the uptake of transferrin, whereas internalization of desmosomal plaques continued. In contrast, actin filaments appeared to be involved in the desmosomal internalization. Thus, depolymerization of actin filaments by cytochalasin D significantly reduced endocytosis of half-desmosomes. Immunogold labeling showed that the vesicles with desmosomal plaques were not enriched in MPR (cation-independent mannose-6-phosphate receptor), cathepsin D or the lysosome-associated membrane protein lamp-1. In addition, the morphology was different. Thus, the endocytic vesicles with desmosomal plaques represent a special compartment, distinct from typical endosomes and lysosomes.
Eur J Cell Biol 1993 Dec
PMID:Endocytosis of desmosomal plaques depends on intact actin filaments and leads to a nondegradative compartment. 792 92

The receptor for insulin-like growth factor type 2, also known as the cation-independent mannose-6-phosphate receptor (Igf2/Mpr), is a multifunctional receptor thought to play a role in lysosomal targeting, cell growth and signal transduction. Igf2/Mpr has been mapped to the mouse Tme locus and shown to be an imprinted gene, which further suggests a role in embryonic growth regulation. To define the functions of Igf2/Mpr, we have generated mice lacking this gene. We report here that maternal inheritance of an Igf2/Mpr null allele (-/+) as well as homozygosity for the inactive allele (-/-) is generally lethal at birth and mutants are about 30% larger, indicating that maternal expression of Igf2/Mpr is essential for late embryonic development and growth regulation. The phenotype is probably caused by an excess of Igf2 because the introduction of an Igf2 null allele rescued the Igf2/Mpr mutant mice. Mutant mice also have organ and skeletal abnormalities and missort mannose-6-phosphate-tagged proteins. A few (-/+) mice reactivated their paternal Igf2/Mpr allele in some tissues and survived to adults. But no (-/-) mice survived, indicating a role for the reactivated paternal allele in postnatal survival.
Nature 1994 Dec 01
PMID:Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. 798 40

The intracellular transport of [125I]tyramine cellobiose low-density lipoprotein ([125ITC]LDL) and [131ITC]beta-very-low-density lipoprotein ([131ITC]beta-VLDL) in rat liver was studied by means of centrifugation in sucrose and Nycodenz gradients. At time-points up to 45 min after intravenous injection, the two ligands were found in endosomes with distinctly different buoyant densities. In the Nycodenz gradients [131ITC]beta-VLDL appeared at 1.08 g/ml partly coinciding with the distribution of the cation independent (alpha)mannose-6-phosphate receptor, whereas [125ITC]LDL was found at 1.13 mg/ml, where the degradation of [125ITC]LDL started. [131ITC]beta-VLDL, on the other hand, was transferred to denser vesicles, banding at 1.16 g/ml, and degradation started in these organelles, similar to that observed with asialoorosomucoid (ASOR) that was used as a control ligand. Since degradation products coincided with beta-N-acetylglucosaminidase we assume that these organelles are secondary lysosomes. [125ITC]LDL was subsequently also transferred to these dense secondary lysosomes, and the distribution of degraded [125ITC]LDL was therefore bimodal until [125ITC]LDL was completely cleared from the circulation. Furthermore our results show that the different intracellular pathways observed are not due to uptake in different liver cell types, since the bimodal distribution of [125ITC]LDL was also evident in purified liver parenchymal cells. The data suggest that LDL and beta-VLDL follow different endosomal pathways in the rat hepatocytes and that both pathways meet in a common final lysosome. The data also support the notion that LDL and beta-VLDL are taken up through different endocytic receptors. However, following estradiol treatment, both ligands seem to follow a common pathway. In this case the density distributions of the two ligands coincide and resemble the pathway of LDL observed in control animals. This may be due to a pronounced up-regulation of LDL receptors following estradiol treatment, and beta-VLDL may under these conditions be taken up via the LDL receptor.
Biochim Biophys Acta 1993 Dec 02
PMID:Endocytosed LDL and beta-VLDL follow different intracellular pathways in rat liver. 825 20

There is little consensus on the nature of the storage compartment of the glucose transporter GLUT4, in non-stimulated cells of muscle and fat. More specifically, it is not known whether GLUT4 is localized to unique, specialized intracellular storage vesicles, or to vesicles that are part of the constitutive endosomal-lysosomal pathway. To address this question, we have investigated the localization of the endogenous GLUT4 in non-stimulated skeletal myotubes from the cell line C2, by immunofluorescence and immunoelectron microscopy. We have used a panel of antibodies to markers of the Golgi complex (alpha mannosidase II and giantin), of the trans-Golgi network (TGN38), of lysosomes (lgp110), and of early and late endosomes (transferrin receptor and mannose-6-phosphate receptor, respectively), to define the position of their subcellular compartments. By immunofluorescence, GLUT4 appears concentrated in the core of the myotubes. It is primarily found around the nuclei, in a pattern suggesting an association with the Golgi complex, which is further supported by colocalization with giantin and by immunogold electron microscopy. GLUT4 appears to be in the trans-most cisternae of the Golgi complex and in vesicles just beyond, i.e. in the structures that constitute the trans-Golgi network (TGN). In myotubes treated with brefeldin A, the immunofluorescence pattern of GLUT4 is modified, but it differs from both Golgi complex markers and TGN38. Instead, it resembles the pattern of the transferrin receptor, which forms long tubules. In untreated cells, double staining for GLUT4 and transferrin receptor by immunofluorescence shows similar but distinct patterns. Immunoelectron microscopy localizes transferrin receptor, detected by immunoperoxidase, to large vesicles, presumably endosomes, very close to the GLUT4-containing tubulo-vesicular elements. In brefeldin A-treated cells, a network of tubules of approximately 70 nm diameter, studded with varicosities, stains for both GLUT4 and transferrin receptor, suggesting that brefeldin A has caused fusion of the transferrin receptor and GLUT4-containing compartments. The results suggest that GLUT4 storage vesicles constitute a specialized compartment that is either a subset of the TGN, or is very closely linked to it. The link between GLUT4 vesicles and transferrin receptor containing endosomes, as revealed by brefeldin A, may be important for GLUT4 translocation in response to muscle stimulation.
J Cell Sci 1996 Dec
PMID:GLUT4 in cultured skeletal myotubes is segregated from the transferrin receptor and stored in vesicles associated with TGN. 900 32

Targeted gene mutations have established distinct, yet overlapping, developmental roles for receptors of the insulin/IGF family. IGF-I receptor mediates IGF-I and IGF-II action on prenatal growth and IGF-I action on postnatal growth. Insulin receptor mediates prenatal growth in response to IGF-II and postnatal metabolism in response to insulin. In rodents, unlike humans, insulin does not participate in embryonic growth until late gestation. The ability of the insulin receptor to act as a bona fide IGF-II-dependent growth promoter is underscored by its rescue of double knockout Igf1r/Igf2r mice. Thus, IGF-II is a true bifunctional ligand that is able to stimulate both insulin and IGF-I receptor signaling, although with different potencies. In contrast, the IGF-II/cation-independent mannose-6-phosphate receptor regulates IGF-II clearance. The growth retardation of mice lacking IGF-I and/or insulin receptors is due to reduced cell number, resulting from decreased proliferation. Evidence from genetically engineered mice does not support the view that insulin and IGF receptors promote cellular differentiation in vivo or that they are required for early embryonic development. The phenotypes of insulin receptor gene mutations in humans and in mice indicate important differences between the developmental roles of insulin and its receptor in the two species.
Endocr Rev 2001 Dec
PMID:Distinct and overlapping functions of insulin and IGF-I receptors. 1173 35

Renin is commonly known as a secretory glycoprotein, which is expressed, stored and released in a regulated manner by the kidney. Besides this, a number of extrarenal tissues, such as adrenal gland and heart express or internalise renin. In the heart a local RAS may exert prohypertrophic, proliferative, antiproliferative or apoptotic properties. The local RAS in kidney, adrenal gland and heart are each unique and their modes of action are distinct. This is due to the expression of different renin transcripts and different intracellular sorting and transport events for renin. In the rat kidney exclusively the commonly known preprorenin is expressed encoding for secretory renin. This is targeted to lysosomes, which become secretory renin granules. The cells of the rat adrenal cortex express preprorenin as well, but this is partially targeted to the regulated secretory pathway. Rat adrenocortical cells additionally express an alternative renin transcript, termed exon1A renin, which encodes for a truncated prorenin that is imported into mitochondria. Its function is not known to date. Interestingly, in the rat heart exclusively the alternative transcript is expressed. Even in hypertrophic hearts or after myocardial infarction, preprorenin remains undetectable. Exon1A renin transcript levels, in contrast, markedly increased after myocardial ischemia. This provides a new molecular basis for a function of locally expressed renin. In addition, there are different pathways of renin internalisation by cardiac cells. A mannose-6-phosphate receptor mediated uptake has been described. We recently described another pathway independently of the mannose-6-phosphate receptor. Such a pathway is apparently of functional significance. Subsequent generation of angiotensins and myocyte hypertrophy and proliferation by prorenin through angiotensin generation has been described.
J Mol Cell Cardiol 2002 Dec
PMID:Intracellular sorting of renin: cell type specific differences and their consequences. 1250 54

PACS-1 is a cytosolic sorting protein that directs the localization of membrane proteins in the trans-Golgi network (TGN)/endosomal system. PACS-1 connects the clathrin adaptor AP-1 to acidic cluster sorting motifs contained in the cytoplasmic domain of cargo proteins such as furin, the cation-independent mannose-6-phosphate receptor and in viral proteins such as human immunodeficiency virus type 1 Nef. Here we show that an acidic cluster on PACS-1, which is highly similar to acidic cluster sorting motifs on cargo molecules, acts as an autoregulatory domain that controls PACS-1-directed sorting. Biochemical studies show that Ser278 adjacent to the acidic cluster is phosphorylated by CK2 and dephosphorylated by PP2A. Phosphorylation of Ser278 by CK2 or a Ser278-->Asp mutation increased the interaction between PACS-1 and cargo, whereas a Ser278-->Ala substitution decreased this interaction. Moreover, the Ser278-->Ala mutation yields a dominant-negative PACS-1 molecule that selectively blocks retrieval of PACS-1-regulated cargo molecules to the TGN. These results suggest that coordinated signaling events regulate transport within the TGN/endosomal system through the phosphorylation state of both cargo and the sorting machinery.
EMBO J 2003 Dec 01
PMID:The phosphorylation state of an autoregulatory domain controls PACS-1-directed protein traffic. 1463 83

This study demonstrates, through a combination of stringent screening methods and thorough validation, that it is possible to identify transmembrane proteins preferentially expressed in primary breast tumour cells. mRNA was extracted from tumour cells isolated from invasive breast cancers and it was then subtracted against normal breast tissue mRNA prior to the generation of a signal sequence-trap library. Screening of the library identified 31 positive clones encoding 12 cell-surface and 12 secreted proteins. The expression of a subset of transmembrane genes was then interrogated using a high-throughput method (tissue microarray) coupled with cutting-edge in situ techniques in a large cohort of patients who had undergone uniform adjuvant chemotherapy. Expression of CD98 heavy chain (CD98HC) and low-level expression of the insulin-like growth factor 2 receptor/mannose-6-phosphate receptor (IGF2R/M6PR) correlated with poor patient prognosis in the whole cohort. Expression of bradykinin receptor B1 (BDKRB1) and testis enhanced gene transcript (TEGT) correlated with good prognosis in woman with oestrogen receptor (ER)-negative breast tumours. These results indicate that this combined approach of isolating primary tumour cells, generating a library to specifically isolate signal-sequence-containing transcripts, and in situ hybridization on tissue microarrays successfully identified novel prognostic markers (BDKRB1, CD98hc, and TEGT) and potential transmembrane therapeutic targets (CD98hc) in breast cancer.
J Pathol 2006 Dec
PMID:Identification of transmembrane proteins as potential prognostic markers and therapeutic targets in breast cancer by a screen for signal sequence encoding transcripts. 1705 9

Although neutral lipid storage droplets are ubiquitous in eukaryotic cells, very little is known about how their synthesis and turnover are controlled. Adipocyte differentiation-related protein (ADRP; also known as adipophilin) is found on the surface of lipid droplets in most mammalian cell types. To learn how ADRP affects lipid storage, we stably expressed the protein in human embryonic kidney 293 (HEK 293) cells, which express little endogenous ADRP. As expected, ADRP was targeted to the surface of lipid droplets and caused an increase in triacylglycerol (TAG) mass under both basal and oleate-supplemented conditions. At least part of the increased mass resulted from a 50% decrease in the rate of TAG hydrolysis in ADRP-expressing cells. Furthermore, ADRP expression increased the fraction of total cellular TAG that was stored in lipid droplets. ADRP expression induced a striking decrease in the association of adipose triglyceride lipase (ATGL) and mannose-6-phosphate receptor tail-interacting protein of 47 kDa with lipid droplets and also decreased the lipid droplet association of several other unknown proteins. Transient expression of ADRP in two other cell lines also reduced the lipid droplet association of catalytically inactive ATGL. We conclude that the reduced lipid droplet association of ATGL and/or other lipases may explain the decrease in TAG turnover observed in ADRP-expressing HEK 293 cells.
J Lipid Res 2007 Dec
PMID:Adipocyte differentiation-related protein reduces the lipid droplet association of adipose triglyceride lipase and slows triacylglycerol turnover. 1787 89

Retrograde transport pathways from early/recycling endosomes to the trans-Golgi network (TGN) are poorly defined. We have investigated the role of TGN golgins in retrograde trafficking. Of the four TGN golgins, p230/golgin-245, golgin-97, GCC185, and GCC88, we show that GCC88 defines a retrograde transport pathway from early endosomes to the TGN. Depletion of GCC88 in HeLa cells by interference RNA resulted in a block in plasma membrane-TGN recycling of two cargo proteins, TGN38 and a CD8 mannose-6-phosphate receptor cytoplasmic tail fusion protein. In GCC88-depleted cells, cargo recycling was blocked in the early endosome. Depletion of GCC88 dramatically altered the TGN localization of the t-SNARE syntaxin 6, a syntaxin required for endosome to TGN transport. Furthermore, the transport block in GCC88-depleted cells was rescued by syntaxin 6 overexpression. Internalized Shiga toxin was efficiently transported from endosomes to the Golgi of GCC88-depleted cells, indicating that Shiga toxin and TGN38 are internalized by distinct retrograde transport pathways. These findings have identified an essential role for GCC88 in the localization of TGN fusion machinery for transport from early endosomes to the TGN, and they have allowed the identification of a retrograde pathway which differentially selects TGN38 and mannose-6-phosphate receptor from Shiga toxin.
Mol Biol Cell 2007 Dec
PMID:The golgin GCC88 is required for efficient retrograde transport of cargo from the early endosomes to the trans-Golgi network. 1791 56


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