USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

作者：Madan Babita; Walker Matthew P; Young Robert; Quick Laura; Orgel Kelly A; Ryan Meagan; Gupta Priti; Henrich Ian C; Ferrer Marc; Marine Shane; Roberts Brian S; Arthur William T; Berndt Jason D; Oliveira Andre M; Moon Randall T^*; Virshup David M^*; Chou Margaret M^*; Major Michael B^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(21): E2945-E2954.

DOI：10.1073/pnas.1605691113

• Wnt signaling
• ubiquitin-specific protease
• USP6
• Frizzled
• ubiquitin

The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. Chromosomal translocations in nodular fasciitis result in USP6 overexpression, leading to transcriptional activation of the Wnt/beta-catenin pathway. Inhibition of Wnt signaling using Dickkopf-1 (DKK1) or a Porcupine (PORCN) inhibitor significantly decreased the growth of USP6-driven xenograft tumors, indicating that Wnt signaling is a key target of USP6 during tumorigenesis. Our study defines an additional route to ectopic Wnt pathway activation in human disease, and identifies a potential approach to modulate Wnt signaling for therapeutic benefit.

• 出版日期2016-5-24
• 单位NIH