Heparan Sulfate Regulates ADAM12 through a Molecular Switch Mechanism

Abstract

The disintegrin and metalloproteases (ADAMs) are emerging as therapeutic targets in human disease, but specific drug design is hampered by potential redundancy. Unlike other metzincins, ADAM prodomains remain bound to the mature enzyme to regulate activity. Here ADAM12, a protease that promotes tumor progression and chondrocyte proliferation in osteoarthritic cartilage, is shown to possess a prodomain/catalytic domain cationic molecular switch, regulated by exogenous heparan sulfate and heparin but also endogenous cell surface proteoglycans and the polyanion, calcium pentosan polysulfate. Sheddase functions of ADAM12 are regulated by the switch, as are proteolytic functions in placental tissue and sera of pregnant women. Moreover, human heparanase, an enzyme also linked to tumorigenesis, can promote ADAM12 sheddase activity at the cell surface through cleavage of the inhibitory heparan sulfate. These data present a novel concept that might allow targeting of ADAM12 and suggest that other ADAMs may have specific regulatory activity embedded in their prodomain and catalytic domain structures.

Heparan Sulfate Chains of Syndecan-1 Regulate Ectodomain Shedding

“…Cell surface heparan sulfate can bind to and inhibit the activity of ADAM12 (A Disintegrin And Metalloprotease 12), a protease that mediates ectodomain shedding of pro-EGF. This inhibition by heparan sulfate occurs via its binding to the ADAM12 catalytic domain (37). However, in contrast to what we found regarding heparan sulfate inhibition of syndecan shedding, ADAM12 activity was also inhibited by exogenous heparin.…”

Sonic hedgehog processing and release are regulated by glypican heparan sulfate proteoglycans

“…Hh sheddase activation by heparan sulfate is further consistent with the known increase of Hh solubilization by Suramine, a polysulfated compound (Etheridge et al, 2010) and with Syndecan 2 (another cell surface HSPG) acting as a docking receptor and activator for MMP7 (Ryu et al, 2009). Moreover, ADAM12 associates with HSPGs through its cysteine-rich domain (Iba et al, 2000), and heparan sulfate binding to ADAM12 transiently activates the enzyme (Sorensen et al, 2008). Finally, heparin activates MMP2 and MMP9 through MT-1 (Butler et al, 1998) and heparan sulfate also activates MMP2 (Koo et al, 2010).…”

Transmembrane Signaling Proteoglycans

“…Several TIMP: tissue inhibitor of metalloproteinase examples of heparan and chondroitin sulfates as potential regulators of metzincin activity exist. ADAM12, ADAM17 (TACE), the aggrecanases ADAMTS4 and 5, and MT3-MMP may be regulated in this way (Dierker et al 2009, Gao et al 2004, Iida et al 2007, Sørensen et al 2008. Syndecan-4 null mice are protected from osteoarthritis in experimental models, perhaps partly as a result of HS-mediated regulation of ADAMTS5 activity (Echtermeyer et al 2009).…”