Activity of the beta-catenin phosphodestruction complex at cell-cell contacts is enhanced by cadherin-based adhesion.
It is well established that cadherin protein levels impact canonical Wnt signaling through binding and sequestering beta-catenin (beta-cat) from T-cell factor family transcription factors. Whether changes in intercellular adhesion can affect beta-cat signaling and the mechanism through which this occurs has remained unresolved. We show that axin, APC2, GSK-3beta and N-terminally phosphorylated forms of beta-cat can localize to cell-cell contacts in a complex that is molecularly distinct from the cadherin-catenin adhesive complex. Nonetheless, cadherins can promote the N-terminal phosphorylation of beta-cat, and cell-cell adhesion increases the turnover of cytosolic beta-cat. Together, these data suggest that cadherin-based cell-cell adhesion limits Wnt signals by promoting the activity of a junction-localized beta-cat phosphodestruction complex, which may be relevant to tissue morphogenesis and cell fate decisions during development.
Maher
Meghan T
MT
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Flozak
Annette S
AS
Stocker
Adam M
AM
Chenn
Anjen
A
Gottardi
Cara J
CJ
D000818:Animals; D060466:Axin Protein; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051820:TCF Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D060466:Axin Protein; D015820:Cadherins; D003598:Cytoskeletal Proteins; D046912:Multiprotein Complexes; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; C117846:adenomatous polyposis coli protein 2; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3