Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin
| Autor: | Daniel S Rivera, Vic E. Myer, Jefferson Parker, Lisa Quinn, Sheri K. Wilcox, Feng Cong, William R. Tschantz, Susanne E. Swalley, Peter LeMotte, Xiaomo Jiang, Andreas Loew, Bo Lu, Christopher A. Dimitri, Melissa Ramones, Olga Charlat, Yang Xie, Jeffrey A. Porter, Mike Watrobka, Brian Granda, Raffaella Zamponi, Doug Jeffery |
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| Rok vydání: | 2013 |
| Předmět: |
Binding Sites
biology Effector Ubiquitin-Protein Ligases HEK 293 cells Amino Acid Motifs Scientific Reports Wnt signaling pathway LRP6 Plasma protein binding Biochemistry Cell biology Receptors G-Protein-Coupled HEK293 Cells Membrane protein Ubiquitin Genetics biology.protein Humans Receptor Thrombospondins Molecular Biology Wnt Signaling Pathway Protein Binding |
| Zdroj: | EMBO reports. 14(12) |
| ISSN: | 1469-3178 |
| Popis: | R-spondin proteins sensitize cells to Wnt signalling and act as potent stem cell growth factors. Various membrane proteins have been proposed as potential receptors of R-spondin, including LGR4/5, membrane E3 ubiquitin ligases ZNRF3/RNF43 and several others proteins. Here, we show that R-spondin interacts with ZNRF3/RNF43 and LGR4 through distinct motifs. Both LGR4 and ZNRF3 binding motifs are required for R-spondin-induced LGR4/ZNRF3 interaction, membrane clearance of ZNRF3 and activation of Wnt signalling. Importantly, Wnt-inhibitory activity of ZNRF3, but not of a ZNRF3 mutant with reduced affinity to R-spondin, can be strongly suppressed by R-spondin, suggesting that R-spondin primarily functions by binding and inhibiting ZNRF3. Together, our results support a dual receptor model of R-spondin action, where LGR4/5 serve as the engagement receptor whereas ZNRF3/RNF43 function as the effector receptor. |
| Databáze: | OpenAIRE |
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