title: The γ-Protocadherin-C3 isoform inhibits canonical Wnt signalling by binding to and stabilizing Axin1 at the membrane.
abstract: The 22 γ-Protocadherin (γ-Pcdh) adhesion molecules encoded by the Pcdhg gene cluster play critical roles in nervous system development, including regulation of dendrite arborisation, neuronal survival, and synaptogenesis. Recently, they have been implicated in suppression of tumour cell growth by inhibition of canonical Wnt signalling, though the mechanisms through which this occurs remain unknown. Here, we show differential regulation of Wnt signalling by individual γ-Pcdhs: The C3 isoform uniquely inhibits the pathway, whilst 13 other isoforms upregulate signalling. Focusing on the C3 isoform, we show that its unique variable cytoplasmic domain (VCD) is the critical one for Wnt pathway inhibition. γ-Pcdh-C3, but not other isoforms, physically interacts with Axin1, a key component of the canonical Wnt pathway. The C3 VCD competes with Dishevelled for binding to the DIX domain of Axin1, which stabilizes Axin1 at the membrane and leads to reduced phosphorylation of Wnt co-receptor Lrp6. Finally, we present evidence that Wnt pathway activity can be modulated up (by γ-Pcdh-A1) or down (by γ-Pcdh-C3) in the cerebral cortex in vivo, using conditional transgenic alleles. Together, these data delineate opposing roles for γ-Pcdh isoforms in regulating Wnt signalling and identify Axin1 as a novel protein interactor of the widely-expressed γ-Pcdh-C3 isoform.
authors.affiliation: Department of Biology, The University of Iowa, 143 Biology Building, Iowa City, 52242, IA, USA.|Integrated Biology Graduate Program, The University of Iowa, 143 Biology Building, Iowa City,52242, IA, USA.
authors.forename: Kar Men
authors.initials: KM
authors.lastname: Mah
authors.affiliation: Department of Biology, The University of Iowa, 143 Biology Building, Iowa City, 52242, IA, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Houston
authors.affiliation: Department of Biology, The University of Iowa, 143 Biology Building, Iowa City, 52242, IA, USA.|Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, 52242, IA, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Weiner
mesh_terms: D060466:Axin Protein / Q000378:metabolism*; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: C555451:AXIN1 protein, human; D060466:Axin Protein; D000070585:Cadherin Related Proteins; D015820:Cadherins; C464785:Gamma-protocadherins; D020033:Protein Isoforms; D051153:Wnt Proteins