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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.
FlyBase ID
FBrf0216910
Publication Type
Research paper
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.
PubMed ID
PubMed Central ID
PMC3171222 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Development
    Title
    Development
    Publication Year
    1987-
    ISBN/ISSN
    0950-1991
    Data From Reference