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Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R‐spondin
Authors:Raffaella Zamponi  Olga Charlat  Melissa Ramones  Susanne Swalley  Xiaomo Jiang  Daniel Rivera  William Tschantz  Bo Lu  Lisa Quinn  Chris Dimitri  Jefferson Parker  Doug Jeffery  Sheri K Wilcox  Mike Watrobka  Peter LeMotte  Brian Granda  Jeffrey A Porter  Vic E Myer  Andreas Loew  Feng Cong
Affiliation:1. Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, , Cambridge, Massachusetts, 02139 USA;2. SomaLogic, Inc., 2945 Wilderness Place, , Boulder, Colorado, 80301 USA
Abstract: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.
Keywords:Wnt  R‐spondin   ZNRF3  RNF43  LGR4
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