title: β-Catenin-dependent pathway activation by both promiscuous "canonical" WNT3a-, and specific "noncanonical" WNT4- and WNT5a-FZD receptor combinations with strong differences in LRP5 and LRP6 dependency.
abstract: The WNT/β-catenin signalling cascade is the best-investigated frizzled receptor (FZD) pathway, however, whether and how specific combinations of WNT/FZD and co-receptors LRP5 and LRP6 differentially affect this pathway are not well understood. This is mostly due to the fact that there are 19 WNTs, 10 FZDs and at least two co-receptors. In our attempt to identify the signalling capabilities of specific WNT/FZD/LRP combinations we made use of our previously reported TCF/LEF Gaussia luciferase reporter gene HEK293 cell line (Ring et al., 2011). Generation of WNT/FZD fusion constructs - but not their separate transfection - without or with additional isogenic overexpression of LRP5 and LRP6 in our reporter cells permitted the investigation of specific WNT/FZD/LRP combinations. The canonical WNT3a in fusion to almost all FZDs was able to induce β-catenin-dependent signalling with strong dependency on LRP6 but not LRP5. Interestingly, noncanonical WNT ligands, WNT4 and WNT5a, were also able to act "canonically" but only in fusion with specific FZDs and with selective dependence on LRP5 or LRP6. These data and extension of this experimental setup to the poorly characterized other WNTs should facilitate deeper insight into the complex WNT/FZD signalling system and its function.
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Pettenkoferstraße 9, 80336 Munich, Germany. Electronic address: larisa.ring@med.uni-muenchen.de.
authors.forename: Larisa
authors.initials: L
authors.lastname: Ring
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Pettenkoferstraße 9, 80336 Munich, Germany. Electronic address: peter.neth@med.uni-muenchen.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Neth
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Pettenkoferstraße 9, 80336 Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80336 Munich, Germany. Electronic address: christian.weber@med.uni-muenchen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Pettenkoferstraße 9, 80336 Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80336 Munich, Germany. Electronic address: sabine.steffens@med.uni-muenchen.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Pettenkoferstraße 9, 80336 Munich, Germany. Electronic address: alexander.faussner@med.uni-muenchen.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Faussner
mesh_terms: D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism; D060528:Wnt4 Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051157:Frizzled Receptors; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D008024:Ligands; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060509:Wnt3A Protein; D060528:Wnt4 Protein; D051176:beta Catenin
keywords: FZD; LRP5/6; WNT; WNT/β-catenin signalling