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Bifurcating action of Smoothened in Hedgehog signaling is mediated by Dlg5.
Chong, Yong Chun; Mann, Randall K; Zhao, Chen; Kato, Masaki; Beachy, Philip A.
Afiliación
  • Chong YC; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA; Department of Developmental Biology, Stanford University, Stanford, California 94305, USA; Department of Biochemistry, Stanford University, Stanford, California 94305, USA;
  • Mann RK; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA; Department of Developmental Biology, Stanford University, Stanford, California 94305, USA; Department of Biochemistry, Stanford University, Stanford, California 94305, USA;
  • Zhao C; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA; Department of Developmental Biology, Stanford University, Stanford, California 94305, USA; Department of Biochemistry, Stanford University, Stanford, California 94305, USA;
  • Kato M; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA; Department of Developmental Biology, Stanford University, Stanford, California 94305, USA;
  • Beachy PA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA; Department of Developmental Biology, Stanford University, Stanford, California 94305, USA; Department of Biochemistry, Stanford University, Stanford, California 94305, USA; Howard Hughes
Genes Dev ; 29(3): 262-76, 2015 Feb 01.
Article en En | MEDLINE | ID: mdl-25644602
Binding of the Hedgehog (Hh) protein signal to its receptor, Patched, induces accumulation of the seven-pass transmembrane protein Smoothened (Smo) within the primary cilium and of the zinc finger transcription factor Gli2 at the ciliary tip, resulting ultimately in Gli-mediated changes in nuclear gene expression. However, the mechanism by which pathway activation is communicated from Smo to Gli2 is not known. In an effort to elucidate this mechanism, we identified Dlg5 (Discs large, homolog 5) in a biochemical screen for proteins that preferentially interact with activated Smo. We found that disruption of Smo-Dlg5 interactions or depletion of endogenous Dlg5 leads to diminished Hh pathway response without a significant impact on Smo ciliary accumulation. We also found that Dlg5 is localized at the basal body, where it associates with another pathway component, Kif7. We show that Dlg5 is required for Hh-induced enrichment of Kif7 and Gli2 at the tip of the cilium but is dispensable for Gpr161 exit from the cilium and the consequent suppression of Gli3 processing into its repressor form. Our findings suggest a bifurcation of Smo activity in Hh response, with a Dlg5-independent arm for suppression of Gli repressor formation and a second arm involving Smo interaction with Dlg5 for Gli activation.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Transducción de Señal / Receptores Acoplados a Proteínas G / Guanilato-Quinasas / Proteínas Hedgehog / Proteínas de la Membrana Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Genes Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 2015 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Transducción de Señal / Receptores Acoplados a Proteínas G / Guanilato-Quinasas / Proteínas Hedgehog / Proteínas de la Membrana Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Genes Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 2015 Tipo del documento: Article