ADAMTS-1/METH-1: A matrix metalloprotease that regulates tumor growth and angiogenesis by selective shedding of cell surface proteins

The role of matrix metalloproteases (MMPs) in tumor biology has undergone considerable change in recent years particularly due to the identification of large subfamilies within the broader MMP superfamily. One such subfamily, the ADAMTS family, is named for its structural homology as proteins that contain A&barbelow; D&barbelow;isintegrin A&barbelow;nd M&barbelow;etalloprotease with T&barbelow;hromboS&barbelow;pondin motifs. This family now comprises over 20 members; however very little is known regarding their biological functions. We have recently cloned one member of this family, ADAMTS-1, through a search for novel proteins that function to inhibit angiogenesis. We have previously found ADAMTS-1 to exhibit inhibitory properties on endothelial cell proliferation as well as bioassays of angiogenesis; however; the molecular mechanisms for these activities are unknown. We have investigated ADAMTS-1 with respect to its activity on VEGF mediated endothelial cell proliferation and in the context of tumor angiogenesis to elucidate its mechanisms of action. We have found that ADAMTS-1 inhibits endothelial cell proliferation through both the binding/sequestering and release of VEGF from the endothelial cell surface. In addition, we have found that ADAMTS-1 potently inhibits tumor growth and angiogenesis by the shedding of proteins from both the tumor and endothelial cell surface. Furthermore, we have identified Syndecan-4 as a target of ADAMTS-1 catalytic activity, and demonstrate that ADAMTS-1's anti-tumor and anti-angiogenic effects are mediated by shedding of syndecan-4 ectodomains. This identifies ADAMTS-1 as the first syndecan-4 sheddase, and provides the first evidence for a physiological consequence of syndecan-4 shedding. These findings have broader implications for the role of matrix metalloproteases in tumor biology, particularly with respect to the development of MMP inhibitors as therapeutic compounds. Moreover, they substantiate the role of heparan-sulfate proteoglycans as positive regulators of tumor growth and angiogenesis.