Thrombin Induces Tumor Invasion through the Induction and Association of Matrix Metalloproteinase-9 and {beta}1-Integrin on the Cell Surface.

Thrombin Induces Tumor Invasion through the Induction and Association of Matrix Metalloproteinase-9 and {beta}1-Integrin on the Cell Surface. Research Abstract Details 

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Thrombin Induces Tumor Invasion through the Induction and Association of Matrix Metalloproteinase-9 and {beta}1-Integrin on the Cell Surface. Abstract Text:

A Reza Radjabi,Kenjiro Sawada,Sujatha Jagadeeswaran,Alfred Eichbichler,Hilary A Kenny,Anthony Montag,Katharina Bruno,Ernst Lengyel,A Reza Radjabi,Kenjiro Sawada,Sujatha Jagadeeswaran,Alfred Eichbichler,Hilary A Kenny,Anthony Montag,Katharina Bruno,Ernst Lengyel,

The procoagulatory serine protease, thrombin, is known to induce invasion and metastasis in various cancers, but the mechanisms by which it promotes tumorigenesis are poorly understood. Because the 92-kDa gelatinase (MMP-9) is a known mediator of tumor cell invasion, we sought to determine whether and how thrombin regulates MMP-9. The thrombin receptor, PAR-1, and MMP-9 are expressed in osteosarcomas, as determined by immunohistochemistry. Stimulation of U2-OS osteosarcoma cells with thrombin and a thrombin receptor-activating peptide induced pro-MMP-9 secretion as well as cell surface-associated pro-MMP-9 expression and proteolytic activity. This was paralleled by an increase in MMP-9 mRNA and MMP-9 promoter activity. Thrombin-induced invasion of U2-OS cells through Matrigel was mediated by the phosphatidylinositol 3-kinase signaling pathway and could be inhibited with an MMP-9 antibody. The stimulation of MMP-9 by thrombin was paralleled by an increase in beta1-integrin mRNA and beta1-integrin expression on the cell surface, which was also mediated by phosphatidylinositol 3-kinase and was required for invasion. Thrombin activation induced and co-localized both beta1-integrin and pro-MMP-9 on the cell membrane, as evidenced by co-immunoprecipitation, confocal microscopy, and a protein binding assay. The thrombin-mediated association of these two proteins, as well as thrombin-mediated invasion of U2-OS cells, could be blocked with a cyclic peptide and with an antibody preventing binding of the MMP-9 hemopexin domain to beta1-integrin. These results suggest that thrombin induces expression and association of beta1-integrin with MMP-9 and that the cell surface localization of the protease by the integrin promotes tumor cell invasion.

Thrombin Induces Tumor Invasion through the Induction and Association of Matrix Metalloproteinase-9 and {beta}1-Integrin on the Cell Surface. Publishing Authors By Initials

AR Radjabi,K Sawada,S Jagadeeswaran,A Eichbichler,HA Kenny,A Montag,K Bruno,E Lengyel,AR Radjabi,K Sawada,S Jagadeeswaran,A Eichbichler,HA Kenny,A Montag,K Bruno,E Lengyel,

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Thrombin Induces Tumor Invasion through the Induction and Association of Matrix Metalloproteinase-9 and {beta}1-Integrin on the Cell Surface. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The Journal of biological chemistry

VOLUME: 283

Page Numbers: 2822-34

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 29

MONTH: 11

YEAR: 2007

Thrombin Induces Tumor Invasion through the Induction and Association of Matrix Metalloproteinase-9 and {beta}1-Integrin on the Cell Surface. Information

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LANGUAGE: eng

NlmUniqueID: 2985121

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AFFILIATION: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, Center for Integrative Science, the Departments of Pathology and Biochemistry and Molecular Biology.

Country: United States

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MEDLINETA: J Biol Chem

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