Reference Report

Reference
Citation	Shi, Q., Li, S., Jia, J., Jiang, J. (2011). The Hedgehog-induced Smoothened conformational switch assembles a signaling complex that activates Fused by promoting its dimerization and phosphorylation. Development 138(19): 4219--4231. (Export to RIS)
FlyBase ID	FBrf0216910
Publication Type	Research paper
PubMed ID	21852395
PubMed Abstract	Hedgehog (Hh) transduces signal by regulating the subcellular localization and conformational state of the GPCR-like protein Smoothened (Smo) but how Smo relays the signal to cytoplasmic signaling components remains poorly understood. Here, we show that Hh-induced Smo conformational change recruits Costal2 (Cos2)/Fused (Fu) and promotes Fu kinase domain dimerization. We find that induced dimerization through the Fu kinase domain activates Fu by inducing multi-site phosphorylation of its activation loop (AL) and phospho-mimetic mutations of AL activate the Hh pathway. Interestingly, we observe that graded Hh signals progressively increase Fu kinase domain dimerization and AL phosphorylation, suggesting that Hh activates Fu in a dose-dependent manner. Moreover, we find that activated Fu regulates Cubitus interruptus (Ci) by both promoting its transcriptional activator activity and inhibiting its proteolysis into a repressor form. We provide evidence that activated Fu exerts these regulations by interfering with the formation of Ci-Sufu and Ci-Cos2-kinase complexes that normally inhibit Ci activity and promote its processing. Taken together, our results suggest that Hh-induced Smo conformational change facilitates the assembly of active Smo-Cos2-Fu signaling complexes that promote Fu kinase domain dimerization, phosphorylation and activation, and that Fu regulates both the activator and repressor forms of Ci.
DOI	10.1242/dev.067959
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Secondary IDs
Language of Publication	English
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Publication Type	Journal
Abbreviation	Development
Title	Development
Publication Year	1987-
ISBN/ISSN	0950-1991
Data from Reference
Alleles (20)
	ci^Scer\UAS.cHb ci^{U.Scer\UAS.T:Ivir\HA1} cos² cos^{Scer\UAS.T:Avic\GFP-YFP} Ecol\lacZ^dpp.BS3.0 Ecol\lacZ^hh-P30 fu^{CC.EE.Scer\UAS.T:Ivir\HA1} fu^{CC.Scer\UAS.T:Ivir\HA1} fu^{CCm.Scer\UAS.T:Ivir\HA1} fu^{EE.Scer\UAS.T:Ivir\HA1} fu^{Scer\UAS.T:Avic\GFP-CFP} fu^{Scer\UAS.T:Avic\GFP-YFP} fu^{Scer\UAS.T:Ivir\HA1} Scer\GAL4^ap-md544 Scer\GAL4^Bx-MS1096 smo³ smo^{C.Scer\UAS.T:Avic\GFP-CFP} Su(fu)^{Scer\UAS.T:Hsap\MYC} T:Avic\GFP^CFP T:Avic\GFP^YFP
Constructs (13)
	P{BS3.0} P{UAS-ci.U.HA} P{UAS-ci-cDNA} P{UAS-cos.YFP} P{UAS-fu.CC.HA} P{UAS-fu.CC-EE.HA} P{UAS-fu.CCm.HA} P{UAS-fu.CFP} P{UAS-fu.EE.HA} P{UAS-fu.YFP} P{UAS-HA-fu.WT} P{UAS-mycSu(fu)} P{UAS-smo.CFP.C}
Genes (11)
	ci cos Ecol\lacZ en fu hh ptc Scer\GAL4 smo Su(fu) T:Ivir\HA1
Insertions (3)
	P{GawB}ap^md544 P{GawB}Bx^MS1096 P{PZ}hh^P30
Natural transposons (1)
	P-element