Low Density Lipoprotein Receptor-related Protein Mediates Endocytic Clearance of Pro-MMP-2·TIMP-2 Complex through a Thrombospondin-independent Mechanism

Emonard, Hervé; Bellon, Georges; Troeberg, Linda; Berton, Alix; Robinet, Arnaud; Henriet, Patrick; Marbaix, Étienne; Kirkegaard, Kirstine; Patthy, László; Eeckhout, Yves; Nagase, Hideaki; Hornebeck, William; Courtoy, Pierre J.

doi:10.1074/jbc.m406792200

Cited by 96 publications

(101 citation statements)

References 67 publications

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“…TIMP-2 can be endocytosed by LRP-1 both as a free inhibitor and in complex with MMP-2 or proMMP-2 (43). Interestingly, binding of TIMP-2 to HT1080 cells was insensitive to RAP, suggesting that TIMP-2 initially binds to a cell surface receptor other than LRP-1 prior to endocytosis (43). Furthermore, endocytosis and degradation of TIMP-2 were only partially inhibited by RAP, indicating that an LRP-1-independent endocytic pathway also occurs (43).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, binding of TIMP-2 to HT1080 cells was insensitive to RAP, suggesting that TIMP-2 initially binds to a cell surface receptor other than LRP-1 prior to endocytosis (43). Furthermore, endocytosis and degradation of TIMP-2 were only partially inhibited by RAP, indicating that an LRP-1-independent endocytic pathway also occurs (43). These studies thus suggest that both TIMP-2 and TIMP-3 can be endocytosed by LRP-1-dependent and LRP-1-independent pathways.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, urokinase plasminogen activator receptor-associated protein/endocytic recycling protein Endo180 is expressed in chondrocytes and fibroblasts and is involved in collagen internalization (40,41). TIMP-1 and TIMP-2 are also endocytosed by LRP-1 (42,43). Whereas TIMP-1 is internalized only in complex with MMP-9, with the binding determinants thought to reside on the MMP-9 (42).…”

Section: Discussionmentioning

confidence: 99%

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Differential Regulation of Extracellular Tissue Inhibitor of Metalloproteinases-3 Levels by Cell Membrane-bound and Shed Low Density Lipoprotein Receptor-related Protein 1

Scilabra

Troeberg

Yamamoto

et al. 2013

Journal of Biological Chemistry

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Background: Tissue inhibitor of metalloproteinases-3 (TIMP-3) is endocytosed, but its regulatory mechanism is not well understood. Results: TIMP-3 endocytosis occurs mainly through low density lipoprotein receptor-related protein-1 (LRP-1), but shed sLRP-1 binds TIMP-3. Conclusion: TIMP-3-sLRP-1 complexes are retained extracellularly with metalloproteinase inhibitory activity. Significance: LRP-1 is the master regulator of extracellular levels of TIMP-3.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Differential Regulation of Extracellular Tissue Inhibitor of Metalloproteinases-3 Levels by Cell Membrane-bound and Shed Low Density Lipoprotein Receptor-related Protein 1

Scilabra

Troeberg

Yamamoto

et al. 2013

Journal of Biological Chemistry

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“…2B, 10 proteins co-purified at significant levels with CCRII and CCRIV when the fusion proteins were expressed in CHO-K1 cells. This list includes known LRP1 ligands such as RAP, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase 2 (37,38) together with previously unidentified LRP1 ligands, such as the proteases matrix metalloproteinase-19 and legumain, and the extracellular matrix proteins SPARC and collagen 5 (col5a2). As anticipated, following GST-RAP treatment, the spectral counts for RAP binding to CCRII and CCRIV increased from 10 to 71 and from 15.2 to 46.2, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…2B). This category included known ligands for LRP1, such as RAP, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase 2 (16,37,38). The most abundant LRP1 ligand discovered in the extracellular protein category is a member of the FGF receptor family: Golgi glycoprotein 1 (GLG1)/cysteine-rich fibroblast growth factor receptor/E-selectin ligand 1.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris

Fernández-Castañeda

Arandjelovic

Stiles

et al. 2013

Journal of Biological Chemistry

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Background: LRP1 is a scavenger receptor involved in the clearance of apoptotic cells and myelin vesicles. Results: Novel ligands for LRP1 were discovered in CNS myelin by affinity purification combined with proteomics. Conclusion: Some ligands are intracellular proteins, suggesting a function for LRP1 in the clearance of necrotic debris. Significance: LRP1 mediates the removal of cellular waste and could maintain homeostasis.

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Thrombospondin‐1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor‐related protein‐1 (LRP‐1)

Greenaway

Lawler

Moorehead

et al. 2006

Journal Cellular Physiology

157

129

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VEGF is a potent pro-angiogenic factor whose effects are opposed by a host of anti-angiogenic proteins, including thrombospondin-1 (TSP-1). We have previously shown that VEGF has important extravascular roles in the ovary and that VEGF and TSP-1 are inversely expressed throughout the ovarian cycle. To date, however, a causal interaction between TSP-1 and VEGF has not been identified. Here, we show that TSP-1 has a direct inhibitory effect on VEGF by binding the growth factor and internalizing it via LRP-1. Mice lacking TSP-1 are subfertile and exhibited ovarian hypervascularization and altered ovarian morphology. Treatment of ovarian cells with TSP-1 decreased VEGF levels and rendered the cells more susceptible to TNFα-induced apoptosis. Knockdown of TSP-1, through RNA interference, resulted in overexpression of VEGF and reduced cytokine-induced apoptosis.In conclusion, we demonstrate a direct inhibitory effect of TSP-1 on VEGF in the ovary. TSP-1's regulation of VEGF appears to be an important mediator of ovarian angiogenesis and follicle development.The growth of normal tissues and pathological structures such as tumors are dependent upon the formation of blood vessels for nutrient delivery and waste removal (Folkman, 1992). Growth of new vasculature is regulated by a balance between pro-and anti-angiogenic factors. A potent pro-angiogenic factor is vascular endothelial growth factor (VEGF), which is a heparin-binding glycoprotein secreted as a homodimer that stimulates endothelial cell proliferation and migration (Bernatchez et al., 2002;Castellon et al., 2002), promotes new vessel formation, increases vascular permeability (Ferrara, 2004), and acts as a survival factor for endothelial cells in vitro and in vivo (Gerber et al., 1998;Jia et al., 2004). In addition to its effects on endothelial cells, we recently reported that VEGF protects ovarian cells from apoptosis by signaling through VEGFR-2 expressed by these cells (Greenaway et al., 2004).The effects of pro-angiogenic factors are balanced by anti-angiogenic factors such as members of the thrombospondin (TSP) family, which consists of five proteins (TSP-1-5), of which TSP-1 and -2 share structural and functional homology (Bornstein, 1992; Adams and Lawler, 2004). TSP-1 is a secreted glycoprotein located in the extracellular matrix that has been shown to be a potent inhibitor of angiogenesis (Lawler, 2002; Armstrong and Bornstein, 2003;Wang et al., 2003;Cursiefen et al., 2004;Lawler and Detmar, 2004 (Detmar, 2000). In addition, a direct interaction of VEGF with TSP-1 and with a TSP-1 type I repeat domain of connective tissue growth factor has been reported (Gupta et al., 1999;Inoki et al., 2002). TSP-1 is also known to bind ligands and interact with the low-density lipoprotein receptorrelated protein (LRP-1), resulting in internalization and degradation of the protein (Mikhailenko et al., 1995;Emonard et al., 2004;Wang et al., 2004). LRP-1 is a member of the low-density lipoprotein receptor gene family, which also includes the LDL, VLDL, and apo...

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Low Density Lipoprotein Receptor-related Protein Mediates Endocytic Clearance of Pro-MMP-2·TIMP-2 Complex through a Thrombospondin-independent Mechanism

Cited by 96 publications

References 67 publications

Differential Regulation of Extracellular Tissue Inhibitor of Metalloproteinases-3 Levels by Cell Membrane-bound and Shed Low Density Lipoprotein Receptor-related Protein 1

Differential Regulation of Extracellular Tissue Inhibitor of Metalloproteinases-3 Levels by Cell Membrane-bound and Shed Low Density Lipoprotein Receptor-related Protein 1

Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris

Thrombospondin‐1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor‐related protein‐1 (LRP‐1)

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