Tissue-type Plasminogen Activator Acts as a Cytokine That Triggers Intracellular Signal Transduction and Induces Matrix Metalloproteinase-9 Gene Expression

Hu, Kebin; Yang, Junwei; Tanaka, Sakae; Gonias, Steven L.; Mars, Wendy M.; Liu, Youhua

doi:10.1074/jbc.m504988200

Cited by 173 publications

(245 citation statements)

References 48 publications

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“…We then investigated pro-cath-D internalization by LRP1 using MEF that lacked M6P receptors ( Figure 1B Pro-cath-D and ectopic cath-D do not modulate LRP1b-chain tyrosine phosphorylation in fibroblasts The LRP1 at the plasma membrane is located in clathrin-coated pits and lipid rafts (Boucher et al, 2002;Zhang et al, 2004;Wu and Gonias, 2005), and it has been suggested that there are LRP1-induced signal transduction pathways triggered by tyrosine phosphorylation or RIP in lipid rafts (Boucher et al, 2002; von Cathepsin D, endocytosis and LRP1 RIP D Derocq et al Arnim et al, 2005;Wu and Gonias, 2005). We observed that LRP1b overproduction directs pro-cath-D to the lipid rafts (Beaujouin et al, 2010), suggesting that cath-D modulates the tyrosine phosphorylation of LRP1, as shown for the PDGF-BB (Boucher et al, 2002;Loukinova et al, 2002;Boucher and Gotthardt, 2004;Newton et al, 2005) and CTGF (Yang et al, 2004) growth factors, the tPA serine protease (Hu et al, 2006) and in fibroblasts transformed with v-Src (Barnes et al, 2001(Barnes et al, , 2003. We next investigated the effect of pro-cath-D on the tyrosine phosphorylation of LRP1b in fibroblasts.…”

Section: Resultssupporting

confidence: 69%

“…It delivers most, but not all, of these ligands to lysosomes for degradation (Herz and Strickland, 2001;Gonias et al, 2004;Emonard et al, 2005;May et al, 2007). It has also been shown that LRP1 is involved in signal transduction by phosphorylation of the tyrosine in the cytoplasmic NPXY motifs of its b-chain and modulation of signaling pathways such as the MAP kinase pathway (Barnes et al, 2001(Barnes et al, , 2003Boucher et al, 2002;Boucher and Gotthardt, 2004;Loukinova et al, 2002;Yang et al, 2004;Newton et al, 2005;Hu et al, 2006). More recent studies have shown that LRP1 influences gene transcription by regulated intramembrane proteolysis (RIP) of its b-chain (May et al, 2002;Kinoshita et al, 2003;von Arnim et al, 2005;Zurhove et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

et al. 2011

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The aspartic protease cathepsin-D (cath-D) is a marker of poor prognosis in breast cancer that is overexpressed and hypersecreted by human breast cancer cells. Secreted procath-D binds to the extracellular domain of the b-chain of the LDL receptor-related protein-1 (LRP1) in fibroblasts. The LRP1 receptor has an 85-kDa transmembrane b-chain and a noncovalently attached 515-kDa extracellular a-chain. LRP1 acts by (1) internalizing many ligands via its a-chain, (2) activating signaling pathways by phosphorylating the LRP1b-chain tyrosine and (3) modulating gene transcription by regulated intramembrane proteolysis (RIP) of its b-chain. LRP1 RIP involves two cleavages: the first liberates the LRP1 ectodomain to give a membrane-associated form, LRP1b-CTF, and the second generates the LRP1b-intracellular domain, LRP1b-ICD, that modulates gene transcription. Here, we investigated the endocytosis of pro-cath-D by LRP1 and the effect of pro-cath-D/LRP1b interaction on LRP1b tyrosine phosphorylation and/or LRP1b RIP. Our results indicate that pro-cath-D was partially endocytosed by LRP1 in fibroblasts. However, pro-cath-D and ectopic cath-D did not stimulate phosphorylation of the LRP1b-chain tyrosine. Interestingly, ectopic cath-D and its catalytically inactive D231N cath-D, and pro-D231N cath-D all significantly inhibited LRP1 RIP by preventing LRP1b-CTF production. Thus, cath-D inhibits LRP1 RIP independently of its catalytic activity by blocking the first cleavage. As cath-D triggers fibroblast outgrowth by LRP1, we propose that cath-D modulates the growth of fibroblasts by inhibiting LRP1 RIP in the breast tumor microenvironment.

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Section: Resultssupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

et al. 2011

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“…Growing evidence suggests t-PA can act as a cytokine and binds to the cell membrane receptor low-density-lipoprotein receptor-related protein-1 (LRP-1). Independent of its proteolytic capacity, binding by t-PA to LRP-1 induces receptor tyrosine phosphorylation, triggers intracellular signal transduction, and induces collagen production by fibroblasts (30)(31)(32)(33). We detected LRP-1 expression in nasal tissue by real-time PCR, and there was no significant difference between UT and NPs from control subjects and patients with CRS(data not shown).…”

Section: Discussionmentioning

confidence: 86%

Excessive Fibrin Deposition in Nasal Polyps Caused by Fibrinolytic Impairment through Reduction of Tissue Plasminogen Activator Expression

Takabayashi

Kato²,

Peters³

et al. 2013

Am J Respir Crit Care Med

147

205

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Rationale: Nasal polyps (NPs) are characterized by intense edema or formation of pseudocysts filled with plasma proteins, mainly albumin. However, the mechanisms underlying NP retention of plasma proteins in their submucosa remain unclear. Objectives: We hypothesized that formation of a fibrin mesh retains plasma proteins in NPs. We assessed the fibrin deposition and expression of the components of the fibrinolytic system in patients with chronic rhinosinusitis (CRS). Methods:We assessed fibrin deposition in nasal tissue from patients with CRS and control subjects by means of immunofluorescence. Fibrinolytic components, d-dimer, and plasminogen activators were measured using ELISA, real-time PCR, and immunohistochemistry. We also performed gene expression and protein quantification analysis in cultured airway epithelial cells. Measurements and Main Results: Immunofluorescence data showed profound fibrin deposition in NP compared with uncinate tissue (UT) from patients with CRS and control subjects. Levels of the cross-linked fibrin cleavage product protein, d-dimer, were significantly decreased in NP compared with UT from patients with CRS and control subjects, suggesting reduced fibrinolysis (P , 0.05). Expression levels of tissue plasminogen activator (t-PA) mRNA and protein were significantly decreased in NP compared with UT from patients with CRS and control subjects (P , 0.01). Immunohistochemistry demonstrated clear reduction of t-PA in NP, primarily in the epithelium and glands. Th2 cytokine-stimulated cultured airway epithelial cells showed down-regulation of t-PA, suggesting a potential Th2 mechanism in NP. Conclusions: A Th2-mediated reduction of t-PA might lead to excessive fibrin deposition in the submucosa of NP, which might contribute to the tissue remodeling and pathogenesis of CRS with nasal polyps.

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“…A number of studies have shown that the role of tPA is far more complex, and as a result, the functional role of tPA has been dramatically revised. It is now believed that tPA also plays an important, plasmin-independent, stimulatory, cytokine-like role responsible for a diverse number of physiological functions, including the regulation of endothelial cell proliferation (13), modulation of neuron apoptosis (14), and transcriptional up-regulation of MMP9 (10,11). It must be said, however, that the multifarious plasmin-dependent and -independent functions of tPA are not mutually exclusive.…”

Section: Discussionmentioning

confidence: 99%

“…tPA is known to signal as a cytokine via LRP, causing increased transcription of MMP9 (10,11). RT-PCR was carried out to assess mesangial cell expression of MMP9 and MMP2 mRNAs in response to ACE-I treatment.…”

Section: Resultsmentioning

confidence: 99%

Perindoprilat Modulates the Activity of Lipoprotein Receptor-related Protein in Human Mesangial Cells

Pawluczyk

Patel

Harris

2008

Journal of Biological Chemistry

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Low density lipoprotein receptor-related protein (LRP) is a multifunctional endocytic receptor implicated in the modulation of a number of cellular processes, including the turnover of proteases and the degradation of extracellular matrix proteins. As such, it can play a key role in the control of fibrosis. The aim of this investigation was to ascertain whether the anti-fibrotic effects exerted by the angiotensin-converting enzyme inhibitor (ACE-I) perindoprilat on macrophage-conditioned medium (MPCM)-injured human mesangial cells can be modulated by this receptor. Addition of receptor-associated protein to MPCM-injured mesangial cells with and without ACE-I increased the amount of tissue plasminogen activator protein detected in mesangial cell culture supernatants without affecting the protein levels of plasminogen activator inhibitor-1. The ability of ACE-I to reduce fibronectin was diminished in the presence of receptor-associated protein. ACE-I induced an increase in mesangial cell MMP9 mRNA, but reduced the MMP9 enzyme activity detected in mesangial cell supernatants. Mesangial cell lysates from ACE-I-treated cells were able to bind immobilized fibronectin at higher dilutions than cell lysates from untreated cells. Flow cytometry showed that MPCM induced an increase in LRP surface expression in mesangial cells over that in control cells and that this expression was further increased by ACE-I treatment. The increase in LRP expression in response to ACE-I was also observed by Western blotting. Northern blot analysis of RNA extracted from cells following a 24-h exposure to MPCM with and without ACE-I demonstrated that there was no change in LRP mRNA expression upon ACE-I treatment. In conclusion, we show that ACE-I treatment is able to modulate mesangial cell-surface expression of LRP, providing an additional mechanism whereby ACE-Is can mediate anti-fibrotic actions independent of their hemodynamic actions.Low density lipoprotein receptor-related protein (LPR) 2 is a widely expressed, multifunctional endocytic and signaling receptor implicated in the modulation of a number of cellular processes, including lipoprotein catabolism, blood coagulation, and cell adhesion and migration (1). Among its many functions, LRP modulates the turnover of proteases and protease inhibitor complexes and is known to be a clearing receptor for tissue plasminogen activator (tPA) (1, 2). LRP expression is also associated with regulating extracellular matrix deposition because it mediates fibronectin catabolism and inhibits fibronectin accumulation on cell surfaces (3). More recently, however, it has been found that these receptors may play an important role in cell signaling (1).We have shown previously that the angiotensin-converting enzyme inhibitor (ACE-I) perindoprilat exerts anti-fibrotic effects in human mesangial cells via the bradykinin/tPA axis (4). In those experiments, perindoprilat was able to reduce macrophage-conditioned medium (MPCM)-induced fibronectin levels while concomitantly up-regulating tPA mRNA levels. Parado...

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Tissue-type Plasminogen Activator Acts as a Cytokine That Triggers Intracellular Signal Transduction and Induces Matrix Metalloproteinase-9 Gene Expression

Cited by 173 publications

References 48 publications

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

Excessive Fibrin Deposition in Nasal Polyps Caused by Fibrinolytic Impairment through Reduction of Tissue Plasminogen Activator Expression

Perindoprilat Modulates the Activity of Lipoprotein Receptor-related Protein in Human Mesangial Cells

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