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Identification of membrane‐bound serine proteinase matriptase as processing enzyme of insulin‐like growth factor binding protein‐related protein‐1 (IGFBP‐rP1/angiomodulin/mac25)

Insulin‐like growth factor (IGF) binding protein‐related protein‐1 (IGFBP‐rP1) modulates cellular adhesion and growth in an IGF/insulin‐dependent or independent manner. It also shows tumor‐suppressive activity in vivo. We recently found that a single‐chain IGFB‐rP1 is proteolytically cleaved to a two‐chain form by a trypsin‐like, endogenous serine proteinase, changing its biological activities. In this study, we attempted to identify the IGFBP‐rP1‐processing enzyme. Of nine human cell lines tested, seven cell lines secreted IGFBP‐rP1 at high levels, and two of them, ovarian clear cell adenocarcinoma (OVISE) and gastric carcinoma (MKN‐45), highly produced the cleaved IGFBP‐rP1. Serine proteinase inhibitors effectively blocked the IGFBP‐rP1 cleavage in the OVISE cell culture. The conditioned medium of OVISE cells did not cleave purified IGFBP‐rP1, but their membrane fraction had an IGFBP‐rP1‐cleaving activity. The membrane fraction contained an 80‐kDa gelatinolytic enzyme, which was identified as the membrane‐type serine proteinase matriptase (MT‐SP1) by immunoblotting. When the membrane fraction was separated by SDS/PAGE, the IGFBP‐rP1‐cleaving activity comigrated with matriptase. A soluble form of matriptase purified in an inhibitor‐free form efficiently cleaved IGFBP‐rP1 at the same site as that found in a naturally cleaved IGFBP‐rP1. Furthermore, small interfering RNAs for matriptase efficiently blocked both the matriptase expression and the cleavage of IGBP‐rP1 in OVISE cells. These results demonstrate that IGFBP‐rP1 is processed to the two‐chain form by matriptase on the cell surface.