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1 Oncology, Georgetown University Medical Center, Washington, DC, USA
* To whom correspondence should be addressed. E-mail: lincy{at}georgetown.edu.
Activation of single-chain, latent matriptase, a type II transmembrane serine protease, depends on the weak proteolytic activity of its own zymogen, as well as its cognate inhibitor, hepatocyte growth factor activator inhibitor 1 (HAI-1). Oligomerization of matriptase zymogens, HAI-1, and probably its interaction with other proteins has been proposed to occur during matriptase activation. In the current study, we examined the cellular events associated with matriptase activation, triggered either by the physiological inducer, sphingosine 1-phosphate (S1P) or by a chemical inducer, the polyanionic compound suramin. S1P-induced matriptase translocation to cell-cell contacts, where it is activated, is an F-actin polymerization-dependent process. Conversely, suramin-induced matriptase accumulation and activation at vesicle-like structures is an F-actin polymerization-independent process. While matriptase activation can occur at different subcellular locations, both S1P- and suramin-induced matriptase accumulation forms unique subcellular structures, termed activation foci, where oligomerization of matriptase zymogens and HAI-1 may occur, promoting matriptase activation. Furthermore, matriptase activation may be regulated by intracellular signaling, since Ro-31-8220, a bisindolylmaleimide protein kinase C inhibitor, inhibited both S1P- and suramin-induced activation. The requirement of HAI-1 for matriptase activation, and the coincidence of HAI-1 and matriptase in activation foci apparently provide rapid access of HAI-1 for inhibition of matriptase, immediately following its activation. Indeed all activated matriptase was detected in complexes with HAI-1, only 5 min after suramin stimulation. The close temporal and spatial coupling of matriptase activation with its inhibition suggests that the proteolytic activity of this enzyme must be well controlled, and that the proteolysis of matriptase substrates may be tightly regulated by this mechanism.
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