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Matriptase activation, an early cellular response to acidosis
I-Chu Tseng1, Han Xu, Feng-Pai Chou
1From the Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, and.
The Journal of Biological Chemistry
|November 27, 2009
Summary
Acidosis rapidly activates matriptase, a protease, in epithelial and carcinoma cells. This novel finding reveals matriptase
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Extracellular acidosis commonly leads to intracellular acidification, altered ion channel activity, and G protein-coupled receptor activation.
- The cellular response to acidosis is complex and not fully understood, particularly regarding protease activation.
Purpose of the Study:
- To investigate the novel cellular response of zymogen activation of matriptase induced by acidosis.
- To characterize the kinetics and cellular localization of acid-induced matriptase activation.
Main Methods:
- Exposure of epithelial and carcinoma cells to pH 6.0 buffer.
- In vitro cell-free assays to assess direct proton effects.
- Analysis of matriptase activation and its inhibition by hepatocyte growth factor activator inhibitor 1 (HAI-1).
- Perturbation of intracellular pH homeostasis using amiloride analogs and diisothiocyanostilbene-2,2'-disulfonic acid.
Main Results:
- Acidosis rapidly and ubiquitously induces matriptase zymogen activation in epithelial and carcinoma cells.
- Matriptase activation occurs within minutes of proton exposure, both extracellularly and intracellularly.
- Activated matriptase is rapidly inhibited by HAI-1 and secreted as stable complexes.
- Intracellular pH changes induced by amiloride analogs and other inhibitors also trigger matriptase activation.
Conclusions:
- Matriptase activation is a novel and rapid cellular response to acidosis.
- Matriptase may function as an early responder to acidosis in epithelial and carcinoma cells.
- This study reveals a new mechanism for regulating proteolysis in response to pH changes.
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