Notch信号通路
细胞生物学
受体
效应器
信号转导
Hes3信号轴
配体(生物化学)
广谱
诱饵
生物
细胞信号
化学
生物化学
组合化学
作者
David González-Pérez,Das S,Daniel Antfolk,Hadia S. Ahsan,Elliot Medina,Carolyn E. Dundes,Rayyan T. Jokhai,Emily D. Egan,Stephen C. Blacklow,Kyle M. Loh,Paulo C. Rodríguez,Vincent C. Luca
标识
DOI:10.1038/s41589-022-01113-4
摘要
The Notch pathway regulates cell fate decisions and is an emerging target for regenerative and cancer therapies. Recombinant Notch ligands are attractive candidates for modulating Notch signaling; however, their intrinsically low receptor-binding affinity restricts their utility in biomedical applications. To overcome this limitation, we evolved variants of the ligand Delta-like 4 with enhanced affinity and cross-reactivity. A consensus variant with maximized binding affinity, DeltaMAX, binds human and murine Notch receptors with 500- to 1,000-fold increased affinity compared with wild-type human Delta-like 4. DeltaMAX also potently activates Notch in plate-bound, bead-bound and cellular formats. When administered as a soluble decoy, DeltaMAX inhibits Notch in reporter and neuronal differentiation assays, highlighting its dual utility as an agonist or antagonist. Finally, we demonstrate that DeltaMAX stimulates increased proliferation and expression of effector mediators in T cells. Taken together, our data define DeltaMAX as a versatile tool for broad-spectrum activation or inhibition of Notch signaling.
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