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      Purified Wnt5a Protein Activates or Inhibits β-Catenin–TCF Signaling Depending on Receptor Context

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      1 , 2 , 1 , 2 ,
      PLoS Biology
      Public Library of Science

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          Abstract

          The Wnts comprise a large class of secreted proteins that control essential developmental processes such as embryonic patterning, cell growth, migration, and differentiation. In the most well-understood “canonical” Wnt signaling pathway, Wnt binding to Frizzled receptors induces β-catenin protein stabilization and entry into the nucleus, where it complexes with T-cell factor/lymphoid enhancer factor transcription factors to affect the transcription of target genes. In addition to the canonical pathway, evidence for several other Wnt signaling pathways has accumulated, in particular for Wnt5a, which has therefore been classified as a noncanonical Wnt family member. To study the alternative mechanisms by which Wnt proteins signal, we purified the Wnt5a protein to homogeneity. We find that purified Wnt5a inhibits Wnt3a protein–induced canonical Wnt signaling in a dose-dependent manner, not by influencing β-catenin levels but by downregulating β-catenin–induced reporter gene expression. The Wnt5a signal is mediated by the orphan tyrosine kinase Ror2, is pertussis toxin insensitive, and does not influence cellular calcium levels. We show that in addition to its inhibitory function, Wnt5a can also activate β-catenin signaling in the presence of the appropriate Frizzled receptor, Frizzled 4. Thus, this study shows for the first time that a single Wnt ligand can initiate discrete signaling pathways through the activation of two distinct receptors. Based on these and additional observations, we propose a model wherein receptor context dictates Wnt signaling output. In this model, signaling by different Wnt family members is not intrinsically regulated by the Wnt proteins themselves but by receptor availability.

          Abstract

          Understanding signaling by Wnt proteins has been hampered by a history of conflicting data. The authors reconcile previous findings concerning Wnt signaling by using purified Wnt5a to probe the signaling pathways it activates.

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          Most cited references56

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          Wnt signaling and cancer.

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            The molecular biology of axon guidance.

            Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.
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              LDL-receptor-related proteins in Wnt signal transduction.

              The Wnt family of secreted signalling molecules are essential in embryo development and tumour formation. The Frizzled (Fz) family of serpentine receptors function as Wnt receptors, but how Fz proteins transduce signalling is not understood. In Drosophila, arrow phenocopies the wingless (DWnt-1) phenotype, and encodes a transmembrane protein that is homologous to two members of the mammalian low-density lipoprotein receptor (LDLR)-related protein (LRP) family, LRP5 and LRP6 (refs 12-15). Here we report that LRP6 functions as a co-receptor for Wnt signal transduction. In Xenopus embryos, LRP6 activated Wnt-Fz signalling, and induced Wnt responsive genes, dorsal axis duplication and neural crest formation. An LRP6 mutant lacking the carboxyl intracellular domain blocked signalling by Wnt or Wnt-Fz, but not by Dishevelled or beta-catenin, and inhibited neural crest development. The extracellular domain of LRP6 bound Wnt-1 and associated with Fz in a Wnt-dependent manner. Our results indicate that LRP6 may be a component of the Wnt receptor complex.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                pbio
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                April 2006
                4 April 2006
                : 4
                : 4
                Affiliations
                [1] 1Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America
                [2] 2Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America
                Cambridge University United Kingdom
                Article
                10.1371/journal.pbio.0040115
                1420652
                16602827
                68c85b1b-ee7a-4aa9-9382-c62b3601bbec
                Copyright: © 2006 Mikels and Nusse. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Categories
                Research Article
                Cancer Biology
                Cell Biology
                Development
                Molecular Biology/Structural Biology
                Biochemistry
                Mus (Mouse)
                Mammals
                Vertebrates
                Animals
                Eukaryotes

                Life sciences
                Life sciences

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