Urokinase-type Plasminogen Activator Receptor (uPAR) Ligation Induces a Raft-localized Integrin Signaling Switch That Mediates the Hypermotile Phenotype of Fibrotic Fibroblasts

Grove, L.; Southern, Brian D.; Jin, Tong‐Shou; White, Kimberly E.; Paruchuri, Sailaja; Harel, Efrat; Wei, Ying; Rahaman, Shaik O.; Gladson, Candece L.; Ding, Qiang; Craik, Charles S.; Chapman, Harold A.; Olman, Mitchell A.

doi:10.1074/jbc.m113.498576

Cited by 34 publications

(36 citation statements)

References 75 publications

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“…FAK is involved in the signaling cascade initiated by integrin receptors and ECM proteins (Parsons et al, 2000;Reiske et al, 2000;Ding et al, 2002). FAK has been identified as a key signaling protein in myofibroblast differentiation, as FAK activation is required for TGF-b1-induced myofibroblast differentiation Ding et al, 2008;Grove et al, 2014). FAK promotes the formation of a-SMA-containing fibers through neuronal Wiskott-Aldrich syndrome protein (Cai et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of Src Kinase in Myofibroblast Differentiation and Pulmonary Fibrosis

Meng

Che

Han

et al. 2014

J Pharmacol Exp Ther

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Myofibroblasts are effector cells in fibrotic disorders that synthesize and remodel the extracellular matrix (ECM). This study investigated the role of the Src kinase pathway in myofibroblast activation in vitro and fibrogenesis in vivo. The profibrotic cytokine, transforming growth factor b1 (TGF-b1), induced rapid activation of Src kinase, which led to myofibroblast differentiation of human lung fibroblasts. The Src kinase inhibitor AZD0530 (saracatinib) blocked TGF-b1-induced Src kinase activation in a dose-dependent manner. Inhibition of Src kinase significantly reduced a-smooth muscle actin (a-SMA) expression, a marker of myofibroblast differentiation, in TGFb1-treated lung fibroblasts. In addition, the induced expression of collagen and fibronectin and three-dimensional collagen gel contraction were also significantly inhibited in AZD0530-treated fibroblasts. The therapeutic efficiency of Src kinase inhibition in vivo was tested in the bleomycin murine lung fibrosis model. Src kinase activation and collagen accumulation were significantly reduced in the lungs of AZD0530-treated mice when compared with controls. Furthermore, the total fibrotic area and expression of a-SMA and ECM proteins were significantly decreased in lungs of AZD0530-treated mice. These results indicate that Src kinase promotes myofibroblast differentiation and activation of lung fibroblasts. Additionally, these studies provide proof-ofconcept for targeting the noncanonical TGF-b signaling pathway involving Src kinase as an effective therapeutic strategy for lung fibrosis.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of Src Kinase in Myofibroblast Differentiation and Pulmonary Fibrosis

Meng

Che

Han

et al. 2014

J Pharmacol Exp Ther

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“…1B). PKH-labeled normal HLFs were allowed to attach to preblocked 10-m sections (25,000 cells per section) of normal and fibrotic lung as previously published (10,31), placed in 1% BSA, serum-free medium (5% CO 2 at 37°C) Ϯ blebbistatin, followed by time-lapse video microscopy on an inverted microscope (Leica DM IRBE). Migration tracking was analyzed using ImagePro software (Media Cybernetics, Rockville, MD).…”

Section: Methodsmentioning

confidence: 99%

Matrix-driven Myosin II Mediates the Pro-fibrotic Fibroblast Phenotype

Southern¹,

Grove²,

Rahaman³

et al. 2016

Journal of Biological Chemistry

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Pro-fibrotic mesenchymal cells are known to be the key effector cells of fibroproliferative disease, but the specific matrix signals and the induced cellular responses that drive the fibrogenic phenotype remain to be elucidated. The key mediators of the fibroblast fibrogenic phenotype were characterized using a novel assay system that measures fibroblast behavior in response to actual normal and fibrotic lung tissue. Using this system, we demonstrate that normal lung promotes fibroblast motility and polarization, while fibrotic lung immobilizes the fibroblast and promotes myofibroblast differentiation. These context-specific phenotypes are surprisingly both mediated by myosin II. The role of myosin II is supported by the observation of an increase in myosin phosphorylation and a change in intracellular distribution in fibroblasts on fibrotic lung, as compared with normal lung. Moreover, loss of myosin II activity has opposing effects on protrusive activity in fibroblasts on normal and fibrotic lung. Loss of myosin II also selectively inhibits myofibroblast differentiation in fibroblasts on fibrotic lung. Importantly, these findings are recapitulated by varying the matrix stiffness of polyacrylamide gels in the range of normal and fibrotic lung tissue. Comparison of the effects of myosin inhibition on lung tissue with that of polyacrylamide gels suggests that matrix fiber organization drives the fibroblast phenotype under conditions of normal/soft lung, while matrix stiffness drives the phenotype under conditions of fibrotic/stiff lung. This work defines novel roles for myosin II as a key regulatory effector molecule of the pro-fibrotic phenotype, in response to biophysical properties of the matrix.

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“…The regulatory effect of uPAR may be exerted through the activation of MAPK, and its overexpression can increase uPA secretion in uPAR-expressing cells, involving its functional interaction with integrins and fMet-Leu-Phe receptors (36). Grove et al (37) observed that uPAR ligation with the urokinase receptor binding domain (amino-terminal fragment) results in enhanced migration of fibroblasts on fibronectin in a protease-independent, lipid raft-dependent manner. Nowicki et al (38) demonstrated that the downregulation of uPA inhibited the phosphatidylinositol 3-kinase and Akt signaling pathways, which led to the migration of glioblastoma cells.…”

Section: A B Cmentioning

confidence: 99%

Effect of urokinase-type plasminogen activator system in gastric cancer with peritoneal metastasis

et al. 2016

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Abstract. Peritoneal metastasis is a primary cause of mortality in patients with gastric cancer. Urokinase-type plasminogen activator (uPA) has been demonstrated to be associated with tumor cell metastasis through the degradation of the extracellular matrix. The present study aimed to investigate the mechanisms of the uPA system in gastric cancer with peritoneal metastasis. Expression of uPA, uPA receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) in four gastric cell lines (AGS, SGC7901, MKN45 and MKN28) was measured by semiquantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay and western blotting. uPA activity was detected using a uPA activity kit. Peritoneal implantation models of rats were established by injecting four gastric cancer cell lines for the selection of the cancer cells with a high planting potential. Biological behaviors, including adhesion, migration and invasion, were determined using a methyl thiazolyl tetrazolium assay. Expression of the uPA system was observed to be highest in the SGC7901 cells among the four gastric cell lines. uPA activity was observed to be highest in the MKN45 cells and lowest in the AGS cells. Furthermore, peritoneal implantation analysis demonstrated that no peritoneal tumors were identified in the AGS cells, whilst the tumor masses observed in the SGC7901 and MKN45 cells were of different sizes. The survival times of the rats injected with the MKN28 and SGC7901 cells were longer than those of the rats injected with the MKN45 cells. Antibodies for uPA, uPAR and PAI-1 in the uPA system had the ability to inhibit the adhesion, migration and invasion of peritoneal metastasis in the gastric cancer cells. The results of the present study demonstrated that the uPA system was positively associated with peritoneal metastasis in gastric cancer.

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Urokinase-type Plasminogen Activator Receptor (uPAR) Ligation Induces a Raft-localized Integrin Signaling Switch That Mediates the Hypermotile Phenotype of Fibrotic Fibroblasts

Cited by 34 publications

References 75 publications

Therapeutic Targeting of Src Kinase in Myofibroblast Differentiation and Pulmonary Fibrosis

Therapeutic Targeting of Src Kinase in Myofibroblast Differentiation and Pulmonary Fibrosis

Matrix-driven Myosin II Mediates the Pro-fibrotic Fibroblast Phenotype

Effect of urokinase-type plasminogen activator system in gastric cancer with peritoneal metastasis

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