Sufu recruits GSK3beta for efficient processing of Gli3.
Hedgehog (Hh) signaling activates the transcription factor Gli by suppressing the function of the suppressor of fused (Sufu) protein in mammals. Here, a novel role of mammalian Sufu is identified where it mediates the phosphorylation of Gli3 by GSK3beta, essential for Gli3 processing to generate a transcriptional repressor for Hh-target genes. Studies using Sufu(-/-) mouse embryonic fibroblasts and siRNA targeting Sufu demonstrate the requirement of Sufu for Gli3 processing. In addition, Sufu can bind to GSK3beta as well as Gli3, and mediates formation of the trimolecular complex Gli3/Sufu/GSK3beta. Thus, Sufu stimulates Gli3 phosphorylation by GSK3beta and Gli3 processing. Furthermore, Sonic Hh stimulation dissociates the Sufu/GSK3beta complex from Gli3, resulting in the blockade of Gli3 processing. Collectively, Sufu presumably functions as a GSK3beta recruiter for Hh-dependent regulation of Gli3 processing. Such a function is very similar to that of Costal2 in Drosophila, suggesting a functional complementation through evolution.
Kise
Yoshiaki
Y
Laboratory of Intracellular Signaling, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, Japan.
Morinaka
Akifumi
A
Teglund
Stephan
S
Miki
Hiroaki
H
D000818:Animals; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D053823:Hedgehog Proteins / Q000378:metabolism; D016547:Kinesins / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074290:Zinc Finger Protein Gli3
D029721:Drosophila Proteins; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C465570:Shh protein, mouse; C490763:Sufu protein, mouse; D000074290:Zinc Finger Protein Gli3; C107452:cos protein, Drosophila; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D016547:Kinesins