title: Bifurcating action of Smoothened in Hedgehog signaling is mediated by Dlg5.
abstract: 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.
authors: 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;
authors: Yong Chun
authors: YC
authors: Chong
authors: 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;
authors: Randall K
authors: RK
authors: Mann
authors: 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;
authors: Chen
authors: C
authors: Zhao
authors: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA; Department of Developmental Biology, Stanford University, Stanford, California 94305, USA;
authors: Masaki
authors: M
authors: Kato
authors: 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 Medical Institute, Stanford University, Stanford, California 94305, USA pbeachy@stanford.edu.
authors: Philip A
authors: PA
authors: Beachy
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D064652:Basal Bodies / Q000378:metabolism; D002460:Cell Line; D002923:Cilia / Q000378:metabolism; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; C523873:Dlg5 protein, mouse; D051528:Guanylate Kinases; C543639:Kif7 protein, mouse; D016547:Kinesins
keywords: Dlg5; Gli; Hedgehog; Kif7; Smoothened; basal body
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