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Tumor Cell Invasion Is Promoted by Activation of Protease Activated Receptor-1 in Cooperation with the αvβ5 Integrin
- Source :
- Journal of Biological Chemistry. 276:10952-10962
- Publication Year :
- 2001
- Publisher :
- Elsevier BV, 2001.
-
Abstract
- The first prototype of the protease activated receptor (PAR) family, the thrombin receptor PAR1, plays a central role both in the malignant invasion process of breast carcinoma metastasis and in the physiological process of placental implantation. The molecular mechanism underlying PAR1 involvement in tumor invasion and metastasis, however, is poorly defined. Here we show that PAR1 increases the invasive properties of tumor cells primarily by increased adhesion to extracellular matrix components. This preferential adhesion is accompanied by the cytoskeletal reorganization of F-actin toward migration-favoring morphology as detected by phalloidin staining. Activation of PAR1 increased the phosphorylation of focal adhesion kinase and paxillin, and the induced formation of focal contact complexes. PAR1 activation affected integrin cell-surface distribution without altering their level of expression. The specific recruitment of alpha(v)beta(5) to focal contact sites, but not of alpha(v)beta(3) or alpha(5)beta(1), was observed by immunofluorescent microscopy. PAR1 overexpressing cells showed selective reciprocal co-precipitation with alpha(v)beta(5) and paxillin but not with alpha(v)beta(3) that remained evenly distributed under these conditions. This co-immunoprecipitation failed to occur in cells containing the truncated form of PAR1 that lacked the entire cytoplasmic portion of the receptor. Thus, the PAR1 cytoplasmic tail is essential for conveying the cross-talk and recruiting the alpha(v)beta(5) integrin. While PAR1 overexpressing cells were invasive in vitro, as reflected by their migration through a Matrigel barrier, invasion was further enhanced by ligand activation of PAR1. Moreover, the application of anti-alpha(v)beta(5) antibodies specifically attenuated this PAR1 induced invasion. We propose that the activation of PAR1 may lead to a novel cooperation with the alpha(v)beta(5) integrin that supports tumor cell invasion.
- Subjects :
- Integrins
Integrin
Transfection
Biochemistry
Focal adhesion
Tumor Cells, Cultured
Humans
Neoplasm Invasiveness
Receptor, PAR-1
Receptors, Vitronectin
Protease-activated receptor
Promoter Regions, Genetic
Beta (finance)
Molecular Biology
Paxillin
Matrigel
biology
Cell Biology
Molecular biology
Cell biology
Gene Expression Regulation, Neoplastic
Protease-Activated Receptor 1
cardiovascular system
biology.protein
Receptors, Thrombin
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 276
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....3d2d22e65180525aa36f6fd716f681f9