uPARAP expression during murine lung development

Smith, Leah; Wagner, Teresa; Huizar, Isham; Schnapp, Lynn M.

doi:10.1016/j.gep.2008.06.006

Cited by 8 publications

(6 citation statements)

References 20 publications

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“…Although uPARAP internalizes collagen I and collagen IV, we previously demonstrated that uPARAP colocalized most closely with collagen IV, not collagen I, during lung development (6). Collagen type IV is a major component of the alveolar basement membrane basal lamina.…”

Section: Discussionmentioning

confidence: 86%

“…We previously demonstrated high expression of uPARAP in the mesenchyme throughout lung development (6). Despite the high expression of uPARAP in the developing lung, development proceeds normally in uPARAP 2/2 mice, and is not associated with any differences in matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinases, or collagen expression in the lung (6).…”

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confidence: 99%

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Role of Urokinase Plasminogen Activator Receptor–Associated Protein in Mouse Lung

Bundesmann

Wagner

Chow

et al. 2012

Am J Respir Cell Mol Biol

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Urokinase plasminogen activator receptor-associated protein (uPARAP, or Endo180) is a transmembrane endocytic receptor that mediates collagen internalization and degradation. uPARAP may be a novel pathway for collagen turnover and matrix remodeling in the lung. The function of uPARAP in lung injury has not been described. We analyzed the pulmonary mechanics of uPARAP 2/2 and wild-type mice at baseline and examined their response after bleomycin instillation. We compared collagen internalization in primary mouse lung fibroblasts (MLFs) from wild-type and uPARAP 2/2 mice using flow cytometry and fluorescent microscopy, and we examined the role of cytokines in regulating uPARAP expression and collagen internalization. We show that uPARAP is highly expressed in the lung, and that uPARAP 2/2 mice have increased lung elastance at baseline and after injury. uPARAP 2/2 mice are protected from changes in lung permeability after acute lung injury and have increased collagen content after bleomycin injury. uPARAP is the primary pathway for internalization of collagens in MLFs. Furthermore, collagen internalization through uPARAP does not require matrix metalloproteinase digestion and is independent of integrins. Mediators of lung injury, including transforming growth factor-b, TNF-a, and IL-1, down-regulate both uPARAP expression and collagen internalization. uPARAP is highly expressed in the murine lung, and loss of uPARAP leads to differences in lung mechanics, lung permeability, and collagen content after injury. uPARAP is required for collagen internalization by MLFs. Thus, uPARAP is a novel pathway that regulates matrix remodeling in the lung after injury.Keywords: urokinase plasminogen activator receptor-associated protein; Endo180; collagen internalization; lung fibroblasts; matrix remodeling Urokinase plasminogen activator receptor-associated protein (uPARAP, Endo180, or mannose receptor, C type 2) is a 180-kD transmembrane receptor that can bind and internalize both fibrillar and nonfibrillar collagens (1, 2). After internalization, uPARAP targets collagen to the lysosome for degradation and then uPARAP recycles to the plasma membrane (3). uPARAP is expressed in mesenchymal cells, predominantly fibroblasts. In addition, dermal macrophage and human placental endothelial cells express low levels of uPARAP (1,4,5).We previously demonstrated high expression of uPARAP in the mesenchyme throughout lung development (6). Despite the high expression of uPARAP in the developing lung, development proceeds normally in uPARAP 2/2 mice, and is not associated with any differences in matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinases, or collagen expression in the lung (6). uPARAP 2/2 mice appear phenotypically normal in the unchallenged state, and have a normal lifespan. One possible explanation for the lack of lung phenotype is use of an alternative pathway for collagen internalization. Although previous work demonstrated that uPARAP was the primary receptor for collagen internalization in dermal fibroblast...

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Section: Discussionmentioning

confidence: 86%

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confidence: 99%

Role of Urokinase Plasminogen Activator Receptor–Associated Protein in Mouse Lung

Bundesmann

Wagner

Chow

et al. 2012

Am J Respir Cell Mol Biol

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“…These include pathological conditions such as cancer, fibrosis and osteoarthritis [17], [21], [22], [23], [24], [25], [26], [27], [28], [29], and under normal physiological conditions, expression has been observed in the developing lung and in the bones [18], [30]. In addition, uPARAP has been found to be functionally involved in protection against tissue fibrosis [21], [28], [29] and in promotion of breast tumor progression [24], [31] and possibly glioma invasion [25].…”

Section: Introductionmentioning

confidence: 99%

Differential Actions of the Endocytic Collagen Receptor uPARAP/Endo180 and the Collagenase MMP-2 in Bone Homeostasis

et al. 2013

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A well-coordinated remodeling of uncalcified collagen matrices is a pre-requisite for bone development and homeostasis. Collagen turnover proceeds through different pathways, either involving extracellular reactions exclusively, or being dependent on endocytic processes. Extracellular collagen degradation requires the action of secreted or membrane attached collagenolytic proteases, whereas the alternative collagen degradation pathway proceeds intracellularly after receptor-mediated uptake and delivery to the lysosomes. In this study we have examined the functional interplay between the extracellular collagenase, MMP-2, and the endocytic collagen receptor, uPARAP, by generating mice with combined deficiency of both components. In both uPARAP-deficient and MMP-2-deficient adult mice the length of the tibia and femur was decreased, along with a reduced bone mineral density and trabecular bone quality. An additional decrease in bone length was observed when combining the two deficiencies, pointing to both components being important for the remodeling processes in long bone growth. In agreement with results found by others, a different effect of MMP-2 deficiency was observed in the distinct bone structures of the calvaria. These membranous bones were found to be thickened in MMP-2-deficient mice, an effect likely to be related to an accompanying defect in the canalicular system. Surprisingly, both of the latter defects in MMP-2-deficient mice were counteracted by concurrent uPARAP deficiency, demonstrating that the collagen receptor does not support the same matrix remodeling processes as the MMP in the growth of the skull. We conclude that both uPARAP and MMP-2 take part in matrix turnover processes important for bone growth. However, in some physiological situations, these two components do not support the same step in the growth process.

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“…This protein, designated uPARAP in the following, is a member of the mannose receptor family of endocytic receptors (22)(23)(24). uPARAP is expressed at sites with ongoing tissue remodeling (25)(26)(27)(28) and functions in delivering collagens for intracellular degradation in lysosomes (29 -35). In some processes the receptor operates together with extracellular collagen degradation mechanisms and it is effective in internalizing the large cleavage products resulting from initial extracellular collagenase digestion (36 -38).…”

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A Novel Functional Role of Collagen Glycosylation

Jürgensen

Madsen

Ingvarsen

et al. 2011

Journal of Biological Chemistry

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Collagens make up the most abundant component of interstitial extracellular matrices and basement membranes. Collagen remodeling is a crucial process in many normal physiological events and in several pathological conditions. Some collagen subtypes contain specific carbohydrate side chains, the function of which is poorly known. The endocytic collagen receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180 plays an important role in matrix remodeling through its ability to internalize collagen for lysosomal degradation. uPARAP/Endo180 is a member of the mannose receptor protein family. These proteins all include a fibronectin type II domain and a series of C-type lectin-like domains, of which only a minor part possess carbohydrate recognition activity. At least two of the family members, uPARAP/Endo180 and the mannose receptor, interact with collagens. The molecular basis for this interaction is known to involve the fibronectin type II domain but nothing is known about the function of the lectin domains in this respect. In this study, we have investigated a possible role of the single active lectin domain of uPARAP/ Endo180 in the interaction with collagens. By expressing truncated recombinant uPARAP/Endo180 proteins and analyzing their interaction with collagens with high and low levels of glycosylation we demonstrated that this lectin domain interacts directly with glycosylated collagens. This interaction is functionally important because it was found to modulate the endocytic efficiency of the receptor toward highly glycosylated collagens such as basement membrane collagen IV. Surprisingly, this property was not shared by the mannose receptor, which internalized glycosylated collagens independently of its lectin function. This role of modulating its uptake efficiency by a specific receptor is a previously unrecognized function of collagen glycosylation.The breakdown and remodeling of the extracellular matrix (ECM) 2 including the basement membrane are important steps in embryonic growth, tissue rearrangements in the healthy body, and invasive cancer growth (1-3). The ECM is composed of a range of different structural proteins, including collagens, laminins, fibronectin, and proteoglycans. The collagens make up by far the most abundant component. Collagens are trimeric proteins that form unique triple helices and assemble into large supramolecular structures such as fibers and sheets, enabling them to form the barriers and structures of the ECM (4).Collagens undergo a range of post-translational modifications, including extensive hydroxylation of prolyl and lysyl residues, N-and O-linked glycosylation, and processing of proforms (5). The hydroxylation of proline and lysine residues plays a role in triple helix stabilization and cross-linking of collagen molecules and the processing of proforms is important for the assembly of collagens into fibrillar structures (6). In contrast, the role of collagen glycosylation is poorly understood. Most is known about the O-linked glycosylation...

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uPARAP expression during murine lung development

Cited by 8 publications

References 20 publications

Role of Urokinase Plasminogen Activator Receptor–Associated Protein in Mouse Lung

Role of Urokinase Plasminogen Activator Receptor–Associated Protein in Mouse Lung

Differential Actions of the Endocytic Collagen Receptor uPARAP/Endo180 and the Collagenase MMP-2 in Bone Homeostasis

A Novel Functional Role of Collagen Glycosylation

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