Wnt enhancing metalloprotease (Wntem), a fly ADAMTS protease, promotes Wnt/Wg signaling

Abstract

ADAM (a disintegrin and metalloproteinase) family plays essential roles in cell proliferation, cancer formation, and metastasis as well as multiple diseases including arthritis and arthrosclerosis. Here, I show that a Drosophila ADAMTS (a disintegrin and metalloproteinase with thrombospondin domains) that we have named Wntem (Wnt enhancing metalloprotease) promotes Wingless (Wg) signaling by involving in the processing of Wg. Wntem has highly conserved domains of ADAMTS family and is processed into two forms, pro-domain and protease domain, respectively. The processed forms containing protease domain were secreted to extracellular matrix (ECM), suggesting that Wntem might function in ECM. The processing of Wntem was carried out autocatalytically as well as by Furin similar to other ADAMTS proteases. Both loss and gain of Wntem function showed lethality throughout the entire developmental stages. This implies that the activity of Wntem has to be tightly regulated for the survival and development of flies and Wntem is suggested as an essential regulator of development. Wnt/Wg is known as one of the key morphogens that is important for not only embryonic development but also tumorogenesis and multiple diseases. Genetic analyses demonstrated that the loss of Wntem reduced Wg signaling, but the gain of Wntem enhanced Wg signaling. Actually, Wntem and Wg were colocalized in early endosomes but not in lysosomes. Furthermore, Wg and active form of Wntem were present on exosomes that are derived from endosomal system. Interestingly, cleaved Wg fragments were present on exosomes in the presence of wild-type Wntem but not in the presence of protease-inactive mutant Wntem. The cleavage occurred in the linker region in between the N-terminal domain (NTD) and the C-terminal domain (CTD) of Wg, raising a possibility that this cleavage somehow enhances Wg activity. Hence, we suggest that Wntem is a new component of exosomes for enhancing Wg signaling.