Tiki proteins are substrates of membrane-type matrix metalloproteinases.

Tiki proteins represent a new family of Wnt-specific proteases that inhibit Wnt signalling by cleaving and inactivating Wnt proteins. Tiki proteins are glycosylphosphatidylinositol (GPI)-anchored proteases and function in both Wnt-producing and Wnt-responsive cells. However, how Tiki proteins are regulated remains elusive. In this study, we demonstrate that matrix metalloproteinase 15 (MMP15) interacts with TIKI2 and degrades TIKI2 on the cell surface. Functionally, MMP15 relieves the inhibitory effect of TIKI2 on Wnt signalling in Wnt-responsive cells. We further show that Tiki proteins are substrates of MMP14, MMP15 and MMP16 but not MMP3 or MMP13. Our study provides insights into the potential regulation of Tiki family proteins by other proteases.