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

We have studied estrogen-regulated proteins in an attempt to understand the mechanism by which estrogens stimulate cell proliferation and mammary carcinogenesis. In estrogen receptor positive human breast cancer cell lines (MCF7, ZR75-1) estrogens specifically increase the production into the culture medium of a 52,000 daltons (52K) glycoprotein. Several high affinity monoclonal antibodies to the partially purified secretory 52K protein have allowed to purify to homogeneity this protein and its cellular processed products. The 52K protein has been identified as the secreted precursor of a cathepsin-D like protease bearing mannose-6-phosphate signals and routed to lysosomes via mannose-6-phosphate receptor. The protease is mitogenic in vitro on estrogen deprived MCF7 cells and is able to degrade basement membrane and proteoglycans following its activation. The cellular related proteins, as detected by immunohistochemistry and immunoassay are more concentrated in proliferative mammary ducts than in resting ducts and their concentration in breast cancer cytosol appears to be more correlated with lymph nodes invasion and disease free survival (with S. Thorpe, Copenhagen) than with the estrogen receptor (RE) level. The protein is also produced constitutively by RE-negative cell lines, while in some antiestrogen resistant variants, it becomes inducible by tamoxifen, contrary to the wild type MCF7 cells. Cloning of its cDNA in lambda gt11 has allowed to show that the mRNA is rapidly induced by estrogens and to sequence the protein and compare it to that of the normal human kidney cathepsin-D.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The estrogen-regulated 52K-cathepsin-D in breast cancer: from biology to clinical applications. 365 55

Cathepsin D is overexpressed in most primary breast cancers where its concentration is correlated with increased metastatic potential. To investigate the possible role and mechanism of this lysosomal protease in metastasis, we transfected low-metastatic rat tumor cells with wild-type human cathepsin D, or mutated forms obtained by insertion of a KDEL peptide signal responsible for ER retention, or a control KDAS peptide. The overexpressed pro-cathepsin D in wild-type and KDAS clones was normally sorted and maturated in lysosomes. In KDEL clones, pro-cathepsin D was mostly retained in the ER or partially secreted by high-producer clones but was not maturated. While overexpressed cathepsin D increased experimental metastasis in athymic mice, the pro-cathepsin/D-KDEL was totally ineffective. Moreover, the effect of cathepsin D on metastasis did not seem to be due to saturation of the mannose-6-phosphate receptor since the secretion of two other rat lysosomal enzymes was unaffected by cathepsin D overexpression. We conclude that pro-cathepsin D overexpression facilitates tumor metastasis only when maturated into an active enzyme.
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PMID:Cathepsin D maturation and its stimulatory effect on metastasis are prevented by addition of KDEL retention signal. 813 16

Transforming growth factor-beta (TGF beta) is a multifunctional growth factor in bone that is secreted as a latent complex and must be activated in order to influence cellular activity. We have investigated the influence of dexamethasone (Dex; a potent glucocorticoid) on the secretion and activation of latent TGF beta by normal human osteoblast-like cells (hOBs). Dex had no significant effect on TGF beta mRNA or total protein production, but treatment with Dex resulted in a steroid dose-dependent activation of up to 90% of the TGF beta produced by the hOBs. Dex-treated hOBs activated multiple latent forms of TGF beta. Conditioned medium from Dex-treated hOBs retained the ability to activate latent TGF beta when incubated at 37 C in the absence of cells. Unlike other cell systems, Dex-induced hOB-mediated TGF beta activation did not involve binding to the mannose-6-phosphate receptor. However, the activation was prevented by treatment of hOB cells with microtubual disrupting agents, by the addition of protease inhibitors, or by weak base treatment of the medium. Dex treatment of hOBs was shown to induce a dose-dependent increase in the mRNA levels of cathepsin-B and -D and in the levels of cathepsin-B protein secreted by the cells. Taken together, these data suggest that Dex treatment of hOBs induces the production and secretion of lysosomal proteases that, when secreted, activate latent TGF beta which is secreted by the hOB cells. There is evidence for an involvement of more than one type of protease in this activation process. This activation of TGF beta may, therefore, play a role in glucocorticoid regulation of bone cell functions. Furthermore, TGF beta is most likely involved in autocrine and paracrine effects on bone cells.
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PMID:Glucocorticoid-induced activation of latent transforming growth factor-beta by normal human osteoblast-like cells. 840 70

The early endosome is the first vacuolar compartment along the endocytic pathway. It is the site of internalization and initial processing of amyloid precursor protein (APP) and apolipoprotein E (ApoE), two proteins of etiological importance in Alzheimer's disease, and a putative site of beta-amyloid peptide (Abeta) formation. Here, we identify early endosomes in human pyramidal neurons, using specific compartmental markers and morphometry, and show that in Alzheimer's disease individual endosomes display up to 32-fold larger volumes than the normal average. Endosomal enlargement contributed to an average 2.5-fold larger total endosomal volume per neuron, implying a marked increase in endocytic activity. Endosomal alterations were evident in most pyramidal neurons in Alzheimer brain, detectable at early stages of the disease but absent in several other neurodegenerative disorders examined. In addition, mature and proenzyme forms of the proteases cathepsin B and cathepsin D, a candidate APP secretase, were identified in most early endosomes in Alzheimer brains but were detectable in only a minor proportion of endosomes in normal brain. Expression of the cation-dependent 46 kDa mannose 6-phosphate receptor was elevated in pyramidal neurons of Alzheimer brains, which could be a possible basis for the altered cathepsin trafficking pattern. Enhanced endocytic activity, coupled with increased trafficking to endosomes of proteases, which may have the ability under pathological conditions to generate Abeta, constitutes a potential mechanism by which beta-amyloidogenesis may become accelerated in sporadic AD and also be subject to influences by ApoE.
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PMID:Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. 923 26

Kaposi's sarcoma-associated herpesvirus (KSHV) is the pathological agent of Kaposi's sarcoma (KS), a tumor characterized by aberrant proliferation of endothelial-cell-derived spindle cells. Since in many cancers tumorigenesis is associated with an increase in the activity of the cathepsin family, we studied the role of cathepsins in KS using an in vitro model of KSHV-mediated endothelial cell transformation. Small-molecule inhibitors and small interfering RNA (siRNA) targeting CTSB, but not other cathepsins, inhibited KSHV-induced postconfluent proliferation and the formation of spindle cells and foci of dermal microvascular endothelial cells. Interestingly, neither CTSB mRNA nor CTSB protein levels were induced in endothelial cells latently infected with KSHV. Secretion of CTSB was strongly diminished upon KSHV infection. Increased targeting of CTSB to endosomes was caused by the induction by KSHV of the expression of insulin-like growth factor-II receptor (IGF-IIR), a mannose-6-phosphate receptor (M6PR) that binds to cathepsins. Inhibition of IGF-IIR/M6PR expression by siRNA released CTSB for secretion. In contrast to the increased cathepsin secretion observed in most other tumors, viral inhibition of CTSB secretion via induction of an M6PR is crucial for the transformation of endothelial cells.
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PMID:Insulin-like growth factor II receptor-mediated intracellular retention of cathepsin B is essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. 1750 77

Rab7b is a recently identified member of the Rab GTPase protein family and has high similarity to Rab7. It has been reported that Rab7b is lysosome associated, that it is involved in monocytic differentiation and that it promotes lysosomal degradation of TLR4 and TLR9. Here we investigated further the localization and function of this GTPase. We found that wild-type Rab7b is lysosome associated whereas an activated, GTP-bound form of Rab7b localizes to the Golgi apparatus. In contrast to Rab7, Rab7b is not involved in EGF and EGFR degradation. Depletion of Rab7b or expression of Rab7b T22N, a Rab7b dominant-negative mutant, impairs cathepsin-D maturation and causes increased secretion of hexosaminidase. Moreover, expression of Rab7b T22N or depletion of Rab7b alters TGN46 distribution, cation-independent mannose-6-phosphate receptor (CI-MPR) trafficking, and causes an increase in the levels of the late endosomal markers CI-MPR and cathepsin D. Vesicular stomatitis virus G protein (VSV-G) trafficking, by contrast, is normal in Rab7b-depleted or Rab7b-T22N-expressing cells. In addition, depletion of Rab7b prevents cholera toxin B-subunit from reaching the Golgi. Altogether, these data indicate that Rab7b is required for normal lysosome function, and, in particular, that it is an essential factor for retrograde transport from endosomes to the trans-Golgi network (TGN).
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PMID:Rab7b controls trafficking from endosomes to the TGN. 2037 62