<i>N</i>-Glycosylation of LRP6 by B3GnT2 Promotes Wnt/β-Catenin Signalling
Ruiyao Xu,
Xianxian Wang,
Sadia Safi,
Nico Braunegger,
Agnes Hipgrave Ederveen,
Michelle Rottmann,
Joachim Wittbrodt,
Manfred Wuhrer,
Janine Wesslowski,
Gary Davidson
Affiliations
Ruiyao Xu
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany
Xianxian Wang
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany
Sadia Safi
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany
Nico Braunegger
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany
Agnes Hipgrave Ederveen
Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
Michelle Rottmann
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany
Joachim Wittbrodt
COS—Centre for Organismal Studies, Department of Molecular Developmental Biology & Physiology, Heidelberg University, Im Neuenheimer Feld 230, 69120 Heidelberg, Germany
Manfred Wuhrer
Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
Janine Wesslowski
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany
Gary Davidson
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany
Reception of Wnt signals by cells is predominantly mediated by Frizzled receptors in conjunction with a co-receptor, the latter being LRP6 or LRP5 for the Wnt/β-catenin signalling pathway. It is important that cells maintain precise control of receptor activation events in order to properly regulate Wnt/β-catenin signalling as aberrant signalling can result in disease in humans. Phosphorylation of the intracellular domain (ICD) of LRP6 is well known to regulate Wntβ-catenin signalling; however, less is known for regulatory post-translational modification events within the extracellular domain (ECD). Using a cell culture-based expression screen for functional regulators of LRP6, we identified a glycosyltransferase, B3GnT2-like, from a teleost fish (medaka) cDNA library, that modifies LRP6 and regulates Wnt/β-catenin signalling. We provide both gain-of-function and loss-of-function evidence that the single human homolog, B3GnT2, promotes extension of polylactosamine chains at multiple N-glycans on LRP6, thereby enhancing trafficking of LRP6 to the plasma membrane and promoting Wnt/β-catenin signalling. Our findings further highlight the importance of LRP6 as a regulatory hub in Wnt signalling and provide one of the few examples of how a specific glycosyltransferase appears to selectively target a signalling pathway component to alter cellular signalling events.
