Tumor Cell Invasion Is Promoted by Activation of Protease Activated Receptor-1 in Cooperation with the αvβ5 Integrin

Sharona Cohen Even-Ram, Miriam Maoz, Elisheva Pokroy, Reuven Reich, Ben Zion Katz, Paul Gutwein, Peter Altevogt, Rachel Bar-Shavit*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

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 αvβ5 to focal contact sites, but not of αvβ3 or α 5β1, was observed by immunofluorescent microscopy. PAR1 overexpressing cells showed selective reciprocal co-precipitation with αvβ5 and paxillin but not with α vβ3 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 αvβ5 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-α vβ5 antibodies specifically attenuated this PAR1 induced invasion. We propose that the activation of PAR1 may lead to a novel cooperation with the αvβ5 integrin that supports tumor cell invasion.

Original languageEnglish
Pages (from-to)10952-10962
Number of pages11
JournalJournal of Biological Chemistry
Volume276
Issue number14
DOIs
StatePublished - 6 Apr 2001
Externally publishedYes

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