Extracellular carriers control lipid-dependent of WNT morphogens

被引:5
作者
Magalhaes, Taciani de Almeida [1 ]
Liu, Jingjing [1 ]
Chan, Charlene [1 ]
Borges, Kleiton Silva [2 ,3 ]
Zhang, Jiuchun [1 ]
Kane, Andrew J. [4 ]
Wierbowski, Bradley M. [1 ]
Ge, Yunhui [5 ]
Liu, Zhiwen [1 ,5 ]
Mannam, Prabhath [2 ]
Zeve, Daniel [2 ,3 ]
Weiss, Ron [4 ]
Breault, David T. [2 ,3 ,6 ]
Huang, Pengxiang [5 ]
Salic, Adrian [1 ]
Liu, Zhiwen [1 ,5 ]
Mannam, Prabhath [2 ]
Zeve, Daniel [2 ,3 ]
Weiss, Ron [4 ]
机构
[1] Harvard Med Sch, Blavatnik Inst, Dept Cell Biol, Boston, MA 02115 USA
[2] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA
[3] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA
[4] MIT, Synthet Biol Ctr, Cambridge, MA 02139 USA
[5] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[6] Harvard Stem Cell Inst, D7 ivin Ave, Cambridge, MA 02138 USA
关键词
FRIZZLED-RELATED PROTEINS; DROSOPHILA ORTHOLOG; STRUCTURAL BASIS; WEB TOOL; HEDGEHOG; MEMBRANE; PATHWAY; CHOLESTEROL; INHIBITION; FRZB-1;
D O I
10.1016/j.devcel.2023.11.027
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 lipiddependent 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.
引用
收藏
页码:244 / +
页数:25
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