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Am J Physiol Cell Physiol (March 30, 2005). doi:10.1152/ajpcell.00076.2005
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Submitted on February 23, 2005
Accepted on March 24, 2005

Hepatocyte growth factor activator inhibitor 1 (HAI-1) regulates activation and expression of matriptase, a membrane-bound serine protease

Michael D Oberst1, Li-Yuan L Chen1, Ken-Ichi Kiyomiya1, Cicely A Williams1, Ming-Shyue Lee1, Michael D Johnson1, Robert B Dickson1, and Chen-Yong Lin1*

1 Oncology/Lombardi Cancer Center, Georgetown University, Medical Center, Washington, DC, USA

* To whom correspondence should be addressed. E-mail: lincy{at}georgetown.edu.

Hepatocyte growth factor activator inhibitor 1 (HAI-1) was initially identified as cognate inhibitor of matriptase, a membrane-bound serine protease. Paradoxically HAI-1 is also required for matriptase activation, a process that requires sphingosine 1-phosphate (S1P)-mediated translocation of the protease to cell-cell junctions in human mammary epithelial cells. In the current study, we further explored how HAI-1 regulates this protease. First we observed that following S1P treatment HAI-1 was co-translocated with matriptase to cell-cell junctions and that the cellular ratio of HAI-1 to matriptase was maintained during this process. However, when this ratio was changed by cell treatment with HAI-1 siRNA or anti-HAI-1 mAb M19, spontaneous activation of matriptase occurred in the absence of S1P-induced translocation; S1P-induced matriptase activation was also enhanced. These results support a role for HAI-1 in protection of cell from uncontrolled matriptase activation. We next expressed matriptase, either alone or with HAI-1 in breast cancer cells that do not endogenously express either protein. A defect in matriptase trafficking to the cell surface occurred if wild type matriptase was expressed in the absence of HAI-1; this defect appeared to result from matriptase toxicity to cells. Coexpression with matriptase of wild type HAI-1, but not HAI-1 mutants altered in its Kunitz domain 1, corrected the trafficking defect. In contrast, catalytically defective matriptase mutants were normal in their trafficking in the absence of HAI-1. These results are also consistent with a role for HAI-1 to prevent inappropriate matriptase proteolytic activity during its protein synthesis and trafficking. Taken together, these results support multiple roles for HAI-1 to regulate matriptase, including its proper expression, intracellular trafficking, activation, and inhibition.




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