Distribution of the ?2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues

Moestrup, Søren K.; Gliemann, Jørgen; Pallesen, Gorm

doi:10.1007/bf00353892

Cited by 385 publications

(268 citation statements)

References 41 publications

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“…The microwave-oven treatment used by us, moreover, may make antigenic determinants on u-PAR accessible to immunochemical detection, by causing dissociation of u-PA/u-PAR and vitronectin/u-PAR complexes. (r2MR/LRP has not hitherto been studied immunohistochemically in breast carcinomas, but Moestrup et al (1992) reported fibroblastic staining and absence of epithelial staining in normal human breast tissue.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical localization of urokinase‐type plasminogen activator, type‐1 plasminogen‐activator inhibitor, urokinase receptor and α2‐macroglobulin receptor in human breast carcinomas

et al. 1996

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We have investigated the localization of urokinase-type plasminogen activator (u-PA), type-I plasminogen-activator inhibitor (PAL I), U-PA receptor (u-PAR) and q-macroglobulinreceptor/low-density-lipoprotein-receptor-related protein (a2MR/LRP) in human breast tumors by immunohistochemical methods. Frozen sections of I33 primary breast carcinomas, 6 ductal carcinomas in situ and 33 lymph-node metastases were stained with monoclonal antibodies. Formalin-fixed sections of I 5 primary tumors and 2 lymph-node metastases were stained with polyclonal antibodies. In primary tumors, u-PA and PAI-I immunoreactivities were intense in macrophages and mast cells, and moderate in benign and malignant epithelial cells as well as in myofibroblasts and endothelial cells. A sub-group of poorly differentiated tumors showed particularly strong staining of stromal fibroblasts. U-PA immunoreactivity was also present in lymphocytes. a,MR/LRP and U-PAR immunoreactivities were intense in macrophages, but apart from these cells, a,MR/LRP was found only in fibroblasts, and U-PAR only in tumor cells located peripherally in tumor-cell clusters and glands and some myofibroblasts in the adjacent stroma. Lymphnode metastases showed staining for u-PA and PAI-I both of cancer cells and of stromal fibroblasts, also staining for U-PA of lymphocytes. Similarly to some of the poorly differentiated primary tumors, approximately half of the metastases showed very strong staining of stromal fibroblasts, and extracts of these metastases had higher U-PA and PAI-I levels, as determined by ELISA, than extracts of metastases without this staining pattern. qMR/LRP was present only in fibroblasts and U-PAR only in some tumor cells. The presence of u-PA, PAI-I, alMR/LRP and U-PAR was controlled biochemically by immunoblotting analyses, ligand-blotting analyses, and direct and reverse zymography. The spatial distribution and the variation in concentration of the various components of the plasminogen-activation system point to a complex, multifunctional role for the 4 proteins in and/or during the development and spread of breast cancer.o 1996 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical localization of urokinase‐type plasminogen activator, type‐1 plasminogen‐activator inhibitor, urokinase receptor and α2‐macroglobulin receptor in human breast carcinomas

et al. 1996

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“…Additionally, both receptors are expressed on antiinflammatory macrophages and co-regulated by glucocorticoids (103,111). However, unlike CD163, the CD91 receptor is expressed on hepatocytes, fibroblasts, and syncytiotrophoblasts in addition to macrophages (110,158). The downstream consequences of heme ingestion in macrophages are not dependent on the mechanism(s) of its delivery to HO-1 (33).…”

Section: Role Of Ho-1 In the Mononuclear Phagocyte Systemmentioning

confidence: 99%

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

Hull

Agarwal

George

2014

Antioxidants & Redox Signaling

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Significance: Heme oxygenase-1 (HO-1) is a potential therapeutic target in many diseases, especially those mediated by oxidative stress and inflammation. HO-1 expression appears to regulate the homeostatic activity and distribution of mononuclear phagocytes ( MP) in lymphoid tissue under physiological conditions. It also regulates the ability of MP to modulate the inflammatory response to tissue injury. Recent Advances: The induction of HO-1 within MP-particularly macrophages and dendritic cells-modulates the effector functions that they acquire after activation. These effector functions include cytokine production, surface receptor expression, maturation state, and polarization toward a pro-or anti-inflammatory phenotype. The importance of HO-1 in MP is emphasized by their expression of specific receptors that primarily function to ingest heme-containing substrate and deliver it to HO-1. Critical Issues: MP are the first immunological responders to tissue damage. They critically affect the outcome of injury to many organ systems, yet few therapies are currently available to specifically target MP during disease pathogenesis. Elucidation of the role of HO-1 expression in MP may help to direct broadly applicable therapies to clinical use that are based on the immunomodulatory capabilities of HO-1. Future Directions: Unraveling the complexities of HO-1 expression specifically within MP will more completely define how HO-1 provides cytoprotection in vivo. The use of models in which HO-1 expression is specifically modulated in bone marrow-derived cells will allow for a more complete characterization of its immunoregulatory properties.

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“…While these receptors have overlapping ligand specificity, they exhibit a different pattern of expression. LRP is widely expressed but prominent in liver and brain (52); VLDL receptor in heart, muscle, adipose tissue, and brain (53); glycoprotein 330 is prominently expressed in specialized epithelia of the brain, lung, and kidney (54,55). Recent studies (11,40) indicate that the VLDL receptor is expressed in the endothelium and probably represents the RAP-sensitive receptor responsible for the catabolism of TSP-1 in these cells.…”

Section: Binding Of 125 I-labeled Tsp-1 To Mef At 4°c Is Inhibited Bymentioning

confidence: 99%

Cellular Internalization and Degradation of Thrombospondin-1 Is Mediated by the Amino-terminal Heparin Binding Domain (HBD)

Mikhailenko

Krylov²,

Argraves

et al. 1997

Journal of Biological Chemistry

106

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Thrombospondin-1 (TSP-1) is a large modular trimeric protein that has been proposed to play a diverse role in biological processes. Newly synthesized TSP-1 either is incorporated into the matrix or binds to the cell surface where it is rapidly internalized and degraded. TSP-1 catabolism is mediated by the low density lipoprotein receptor-related protein (LRP), a large endocytic receptor that is a member of the low density lipoprotein receptor family. Using adenovirus-mediated gene transfer experiments, we demonstrate that the very low density lipoprotein receptor can also bind and internalize TSP-1. An objective of the current investigation was to identify the portion of TSP-1 that binds to these endocytic receptors. The current studies found that the amino-terminal heparin binding domain (HBD, residues 1-214) of mouse TSP-1, when prepared as a fusion protein with glutathione S-transferase (GST), bound to purified LRP with an apparent K D ranging from 10 to 25 nM. Recombinant HBD (rHBD) purified following proteolytic cleavage of GST-HBD, also bound to purified LRP, but with an apparent K D of 830 nM. The difference in affinity was attributed to the fact that GST-HBD exists in solution as a dimer, whereas rHBD is a monomer. Like TSP-1, 125 I-labeled GST-HBD or 125 I-labeled rHBD were internalized and degraded by wild type fibroblasts that express LRP, but not by fibroblasts that are genetically deficient in LRP. The catabolism of both 125 I-labeled GST-HBD and rHBD in wild type fibroblast was blocked by the 39-kDa receptor-associated protein, an inhibitor of LRP function. GST-HBD and rHBD both completely blocked catabolism of 125 I-labeled TSP-1 in a dose-dependent manner, as did antibodies prepared against the HBD. Taken together, these data provide compelling evidence that the amino-terminal domain of TSP-1 binds to LRP and thus the recognition determinants on TSP-1 for both LRP and for cell surface proteoglycans reside within the same TSP-1 domain. Further, high affinity binding of TSP-1 to LRP likely results from the trimeric structure of TSP-1.Thrombospondin-1 (TSP-1) 1 is a large glycoprotein composed of three identical subunits, which are covalently linked by interchain disulfide bonds. This molecule is a part of a family of proteins that currently consists of five members (for reviews, see Refs. 1-3). Each subunit of TSP-1 is composed of an aminoterminal heparin binding domain, a type I procollagen homology region, three properdin repeats, three epidermal growth factor-like repeats, seven calcium binding repeats, and a carboxyl-terminal domain (4). TSP-1 has been proposed to play a diverse role in numerous biological processes; these include embryonic development (5), angiogenesis (6), and hemostasis (7,8). The ability of TSP-1 to influence these biological processes has been attributed to its capacity to bind to matrix proteins, proteinases, growth factors, and cell surface receptors.Given that TSP-1 appears to influence a large number of biological processes, it is not surprising that levels of TSP-1 ar...

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Distribution of the ?2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues

Cited by 385 publications

References 41 publications

Immunohistochemical localization of urokinase‐type plasminogen activator, type‐1 plasminogen‐activator inhibitor, urokinase receptor and α2‐macroglobulin receptor in human breast carcinomas

Immunohistochemical localization of urokinase‐type plasminogen activator, type‐1 plasminogen‐activator inhibitor, urokinase receptor and α2‐macroglobulin receptor in human breast carcinomas

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

Cellular Internalization and Degradation of Thrombospondin-1 Is Mediated by the Amino-terminal Heparin Binding Domain (HBD)

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