Document Detail

Cleavage of Hepatocyte Growth Factor Activator Inhibitor-1 by Membrane-Type MMP-1 Activates Matriptase.
MedLine Citation:
PMID:  22118498     Owner:  NLM     Status:  Publisher    
Co-expression of membrane-type matrix metalloproteinase-1 (MT1-MMP) with hepatocyte growth factor (HGF) activator inhibitor-1 (HAI-1) in HEK293T cells resulted in cleavage of HAI-1 to produce 3 fragments. Recombinant MT1-MMP was shown to cleave HAI-1 protein in vitro. HAI-1 was initially identified as the cognate inhibitor of matriptase, which is a transmembrane serine protease and processes urokinase-type plasminogen activator (uPA). Co-expression of HAI-1 with matriptase suppressed matriptase protease activity, and co-expression of MT1-MMP with them resulted in recovery of matriptase activity by stimulating shedding of HAI-1 fragments. Matriptase protein was detected in squamous carcinoma-derived HSC-4 cells, however, matriptase protease activity was undetectable. Transfection of small interfering RNA (siRNA) for HAI-1 enhanced serine protease activity, which was suppressed by co-transfection of matriptase siRNA. Collagen-gel culture or treatment with Concanavalin A (ConA) of HSC-4 cells enhanced MT1-MMP activity, which induced shedding of HAI-1 fragments and conversely stimulated uPA activation by these cells. Serine protease activity including uPA activation of cells treated with ConA was abrogated by down-regulation of either matriptase or MT1-MMP through the transfection of each siRNA. These results suggest that MT1-MMP induced by collagen-gel culture or ConA treatment causes cleavage and shedding of HAI-1 protein, which allows activation of matriptase in HSC-4 cells. HSC-4 cells showed a characteristic invasive growth by forming vacuole-like structures in collagen gel, which was suppressed by transfection of siRNA for either MT1-MMP or matriptase, suggesting that activation of matriptase through the cleavage of HAI-1 is one of the MT1-MMP multifunctions essential for invasive growth of HSC-4 cells.
Takahiro Domoto; Takahisa Takino; Luyang Guo; Hiroshi Sato
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-11-26
Journal Detail:
Title:  Cancer science     Volume:  -     ISSN:  1349-7006     ISO Abbreviation:  -     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2011 Japanese Cancer Association.
Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
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