ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3

ADAMs are a family of multidomain proteins having proteolytic and cell adhe sion activities. We have previously shown that ADAM 12-S, the secreted solu ble form of human ADAM: 12, is a catalytically active protease. We now desc ribe the purification of full-length recombinant ADAM 12-S and demonstrate that it cleaves insulin-like growth factor binding protein-3 (IGFBP-3). Thi s result supports a role for ADAM 12-5 in the degradation of IGFBP-3 in the blood of pregnant women. Furthermore, we tested for proteolysis of other m embers of the IGF binding protein family and found that ADAM: 12-S cleaves IGFBP-5 in addition to IGFBP-3, but does not cleave IGFBP-1, -2, -4, or -6. ADAM 12-5 may therefore be the IGFBP-5 protease that is secreted by osteob lasts and other cells. Cleavage of both IGFBP-3 and -5 by ADAM 12-5 was inh ibited by TIMP-3, raising the possibility that TIMP-3 is a physiological in hibitor of ADAM 12-5. (C) 2000 Academic Press.