Extracellular carriers control lipid-dependent secretion, delivery, and activity of WNT morphogens.

Developmental cell 2024 Jan 22

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WNT morphogens trigger signaling pathways fundamental for embryogenesis, regeneration, and cancer. WNTs are modified with palmitoleate, which is critical for binding Frizzled (FZD) receptors and activating signaling. However, it is unknown how WNTs are released and spread from cells, given their strong lipid-dependent membrane attachment. We demonstrate that secreted FZD-related proteins and WNT inhibitory factor 1 are WNT carriers, potently releasing lipidated WNTs and forming active soluble complexes. WNT release occurs by direct handoff from the membrane protein WNTLESS to the carriers. In turn, carriers donate WNTs to glypicans and FZDs involved in WNT reception and to the NOTUM hydrolase, which antagonizes WNTs by lipid moiety removal. WNT transfer from carriers to FZDs is greatly facilitated by glypicans that serve as essential co-receptors in Wnt signaling. Thus, an extracellular network of carriers dynamically controls secretion, posttranslational regulation, and delivery of WNT morphogens, with important practical implications for regenerative medicine. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Taciani de Almeida Magalhaes, Jingjing Liu, Charlene Chan, Kleiton Silva Borges, Jiuchun Zhang, Andrew J Kane, Bradley M Wierbowski, Yunhui Ge, Zhiwen Liu, Prabhath Mannam, Daniel Zeve, Ron Weiss, David T Breault, Pengxiang Huang, Adrian Salic. Extracellular carriers control lipid-dependent secretion, delivery, and activity of WNT morphogens. Developmental cell. 2024 Jan 22;59(2):244-261.e6