ADAMTS Sol narae cleaves extracellular Wingless to generate a novel active form that regulates cell proliferation in Drosophila

Abstract

s Wnt/ Wingless (Wg) is essential for embryonic development and adult homeostasis in all metazoans, but the mechanisms by which secreted Wnt/Wg is processed remain largely unknown. A Drosophila Sol narae (Sona) is a member of A D isintegrin A nd M etalloprotease with T hrombo S pondin motif (ADAMTS) family, and positively regulates Wg signaling by promoting Wg secretion. Here we report that Sona and Wg are secreted by both conventional Golgi and exosomal transports, and Sona cleaves extracellular Wg at the two specific sites, leading to the generation of N-terminal domain (NTD) and C-terminal domain (CTD) fragments. The cleaved forms of extracellular Wg were detected in the extracellular region of fly wing discs, and its level was substantially reduced in sona mutants. Transient overexpression of Wg-CTD increased wing size while prolonged overexpression caused lethality and developmental defects. In contrast, Wg-NTD did not induce any phenotype. Moreover, the wing defects and lethality induced by sona RNAi were considerably rescued by Wg-CTD, indicating that a main function of extracellular Sona is the generation of Wg-CTD. Wg-CTD stabilized cytoplasmic Armadillo (Arm) and had genetic interactions with components of canonical Wg signaling. Wg-CTD also induced Wg downstream targets such as Distal-less (Dll) and Vestigial (Vg). Most importantly, Cyclin D (Cyc D) was induced by Wg-CTD but not by full-length Wg. Because Sona also induces Cyc D in a cell non-autonomous manner, Wg-CTD generated by Sona in the extracellular region activates a subset of Wg signaling whose major function is the regulation of cell proliferation.

POU domain motif3 (Pdm3) induces wingless (wg) transcription and is essential for development of larval neuromuscular junctions in Drosophila

“…Further analysis of sona suppressors revealed that sona itself and most suppressors are linked to Wg signaling 12,13 , which raised an interesting possibility that Pdm3 is also involved in Wg signaling. We noticed that pdm3 mutant larvae are slow in locomotion (Movie 1), implying a potential role of pdm3 in NMJ.…”

“…We identified a new pdm3 allele, pdm3 m7 , as a suppressor of lethality induced by Sol narae (Sona) overexpression in a genetic screen. Sona is a fly ADAMTS (A disintegrin and metalloprotease with thrombospondin motif) whose family members are secreted metalloproteases important for cell proliferation, cell survival and development [12][13][14] . We have shown that Sona positively regulates Wingless (Wg) signaling and is essential for fly development, cell survival, and Wg processing [12][13][14] .…”

“…Sona is a fly ADAMTS (A disintegrin and metalloprotease with thrombospondin motif) whose family members are secreted metalloproteases important for cell proliferation, cell survival and development [12][13][14] . We have shown that Sona positively regulates Wingless (Wg) signaling and is essential for fly development, cell survival, and Wg processing [12][13][14] . Wg is a prototype of Wnt family that initiates signal transduction cascade as extracellular signaling proteins, and activation of Wnt signaling leads to transcriptional induction of multiple genes for regulation of cell proliferation, cell survival, cell fate decision, and cell migration [15][16][17] .…”

The kinesin motor Klp98A mediates apical to basal Wg transport

“…In addition to HSPGs, Wg receptor Dfz2 also predominantly localizes to the basal epithelium surface, from where it is endocytosed for signal initiation (Hemalatha et al, 2016). Interestingly, the Drosophila metalloproteinase Sol Narae (Sona) localizes to the basal extracellular matrix of the wing epithelium, where it cleaves extracellular Wg (Kim et al, 2016;Won et al, 2019). The resulting Wg-C-terminal fragment induces a discrete subset of Wg response genes to regulate cell proliferation specifically (Won et al, 2019).…”

A metalloproteinase of the disintegrin and metalloproteinases and the ThromboSpondin Motifs 6 as a novel marker for colon cancer: functional experiments

“…By probing the biological mechanisms of colon cancer, a number of related genes, including oncogenes and tumor suppressor genes have been identified (Xu G et al, 2017). A metalloproteinase of7 the disintegrin and metalloproteinases and the ThromboSpondin Motifs (ADAMTS) family contains 19 members, all of which retain a broadly similar modular structure (Kelwick et al, 2015;Won et al, 2019). According to the study of (Wang et al, 2011), ADAMTS12 expression exerted important impacts on suppressing colorectal cancer development.…”