Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling.
Cell
; 184(8): 2103-2120.e31, 2021 04 15.
Article
en En
| MEDLINE
| ID: mdl-33740419
ABSTRACT
During cell migration or differentiation, cell surface receptors are simultaneously exposed to different ligands. However, it is often unclear how these extracellular signals are integrated. Neogenin (NEO1) acts as an attractive guidance receptor when the Netrin-1 (NET1) ligand binds, but it mediates repulsion via repulsive guidance molecule (RGM) ligands. Here, we show that signal integration occurs through the formation of a ternary NEO1-NET1-RGM complex, which triggers reciprocal silencing of downstream signaling. Our NEO1-NET1-RGM structures reveal a "trimer-of-trimers" super-assembly, which exists in the cell membrane. Super-assembly formation results in inhibition of RGMA-NEO1-mediated growth cone collapse and RGMA- or NET1-NEO1-mediated neuron migration, by preventing formation of signaling-compatible RGM-NEO1 complexes and NET1-induced NEO1 ectodomain clustering. These results illustrate how simultaneous binding of ligands with opposing functions, to a single receptor, does not lead to competition for binding, but to formation of a super-complex that diminishes their functional outputs.
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Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Moléculas de Adhesión Celular Neuronal
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Proteínas Oncogénicas
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Proteínas Ligadas a GPI
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Proteínas del Tejido Nervioso
Tipo de estudio:
Guideline
Idioma:
En
Revista:
Cell
Año:
2021
Tipo del documento:
Article