Regulation of planar cell polarity by Smurf ubiquitin ligases.
Planar cell polarity (PCP) is critical for morphogenesis in metazoans. PCP in vertebrates regulates stereocilia alignment in neurosensory cells of the cochlea and closure of the neural tube through convergence and extension movements (CE). Noncanonical Wnt morphogens regulate PCP and CE in vertebrates, but the molecular mechanisms remain unclear. Smurfs are ubiquitin ligases that regulate signaling, cell polarity and motility through spatiotemporally restricted ubiquitination of diverse substrates. Here, we report an unexpected role for Smurfs in controlling PCP and CE. Mice mutant for Smurf1 and Smurf2 display PCP defects in the cochlea and CE defects that include a failure to close the neural tube. Further, we show that Smurfs engage in a noncanonical Wnt signaling pathway that targets the core PCP protein Prickle1 for ubiquitin-mediated degradation. Our work thus uncovers ubiquitin ligases in a mechanistic link between noncanonical Wnt signaling and PCP/CE.
Narimatsu
Masahiro
M
Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada, M5G 1X5.
Bose
Rohit
R
Pye
Melanie
M
Zhang
Liang
L
Miller
Bryan
B
Ching
Peter
P
Sakuma
Rui
R
Luga
Valbona
V
Roncari
Luba
L
Attisano
Liliana
L
Wrana
Jeffrey L
JL
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002465:Cell Movement; D016764:Cell Polarity; D003051:Cochlea / Q000166:cytology / Q000196:embryology; D000072261:Dishevelled Proteins; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D054259:Neural Tube / Q000196:embryology; D009436:Neural Tube Defects / Q000196:embryology; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D000072261:Dishevelled Proteins; D060588:LIM Domain Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C524253:Prickle1 protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; C492381:Smurf1 protein, mouse; C533325:Smurf2 protein, mouse; D044767:Ubiquitin-Protein Ligases