LGR4 and LGR5 are R‐spondin receptors mediating Wnt/β‐catenin and Wnt/PCP signalling

Andrei Glinka, Christine Dolde, Nadine Kirsch, Ya‐Lin Huang, Olga Kazanskaya, Dierk Ingelfinger, Michael Boutros, Cristina‐Maria Cruciat, Christof Niehrs

Author Affiliations

  1. Andrei Glinka1,
  2. Christine Dolde1,
  3. Nadine Kirsch1,
  4. Ya‐Lin Huang1,
  5. Olga Kazanskaya1,
  6. Dierk Ingelfinger2,
  7. Michael Boutros2,
  8. Cristina‐Maria Cruciat (c.cruciat{at}*,1 and
  9. Christof Niehrs (niehrs{at}*,1,3
  1. 1 Division of Molecular Embryology, DKFZ‐‐ZMBH Alliance, DKFZ, Im Neuenheimer Feld 580, Heidelberg, D‐69120, Germany
  2. 2 Division of Signalling and Functional Genomics, DKFZ and University of Heidelberg, Im Neuenheimer Feld 580, Heidelberg, D‐69120, Germany
  3. 3 Institute of Molecular Biology, Mainz, 55128, Germany
  1. * Tel: +49 6221 42 4391; Fax: +49 6221 42 4692; E‐mail: c.cruciat{at}

    Tel: +49 6221 42 4690; Fax: +49 6221 42 4692; E‐mail: niehrs{at}


R‐spondins are secreted Wnt signalling agonists, which regulate embryonic patterning and stem cell proliferation, but whose mechanism of action is poorly understood. Here we show that R‐spondins bind to the orphan G‐protein‐coupled receptors LGR4 and LGR5 by their Furin domains. Gain‐ and loss‐of‐function experiments in mammalian cells and Xenopus embryos indicate that LGR4 and LGR5 promote R‐spondin‐mediated Wnt/β‐catenin and Wnt/PCP signalling. R‐spondin‐triggered β‐catenin signalling requires Clathrin, while Wnt3a‐mediated β‐catenin signalling requires Caveolin‐mediated endocytosis, suggesting that internalization has a mechanistic role in R‐spondin signalling.

  • Received July 14, 2011.
  • Revision received August 8, 2011.
  • Accepted August 10, 2011.