TH8, a new ADAMTS like protease in Wg signaling pathway. Go-Woon Kim, Jong-Hoon Won, Ok-Kyung Lee, Orkhon Tsogtbaatar, Su-Jin Nam, Yeon Kim, Kyung-Ok Cho. Department of Biological Sciences, KAIST, Daejeon, Republic of Korea.

   Proper regulation of cell division and cell survival is crucial for preventing cancer or abnormal cell death. Evidence is accumulating that ADAMTS (a disintegrin and metalloproteinase with thrombospondin domains) family of metalloproteases play roles in the promotion or suppression of cancer formation and metastasis. We have recently discovered a novel Drosophila metalloprotease named TH8, whose sequence has high homology to ADAMTS family proteins. To understand the function of TH8 protein, we have generated deletion mutants in the th8 gene by imprecise excision of P element, and found that loss of th8 function results in lethality. Similar phenotype was also obtained by RNAi expression. At cellular level, the loss of th8 function causes apoptosis, indicating that TH8 is essential for inhibiting cell death. To understand the underlying mechanism of TH8, we carried out a genetic screen to search for suppressors of th8 over-expression-induced lethal phenotype. One of the suppressor lines had mutation in the wntless (Wls) gene that plays an important role in secretion and uptake of wingless (Wg), suggesting that TH8 also participates in the same process. Indeed, loss of TH8 function decreased Wg signaling and, genetic interactions between TH8 and Wg signaling components such as Dishevelled or Van Gogh/Strabismus were observed. Activation of TH8 strictly depended on Wls, demonstrating the one of biochemical functions of Wls is the cleavage of TH8 prodomain either directly or indirectly. We propose that TH8 is one of essential components in regulating Wg secretion or uptake.