title: Arhgap36-dependent activation of Gli transcription factors.
abstract: Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are up-regulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers.
authors.affiliation: Departments of Chemical and Systems Biology.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Rack
authors.affiliation: Departments of Chemical and Systems Biology.
authors.forename: Jun
authors.initials: J
authors.lastname: Ni
authors.affiliation: Departments of Chemical and Systems Biology.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Payumo
authors.affiliation: Departments of Pediatrics andNeurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regenerative Medicine, University of California, San Francisco, CA 94143;
authors.forename: Vien
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Departments of Chemical and Systems Biology.
authors.forename: J Aaron
authors.initials: JA
authors.lastname: Crapster
authors.affiliation: Divisions of Molecular Genetics and.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Pediatric Neurooncology, German Cancer Research Center, 69120 Heidelberg, Germany; and.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Pediatric Neurooncology, German Cancer Research Center, 69120 Heidelberg, Germany; and.
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Biochemistry, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: John K
authors.initials: JK
authors.lastname: Mich
authors.affiliation: Departments of Chemical and Systems Biology.
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Firestone
authors.affiliation: Pediatric Neurooncology, German Cancer Research Center, 69120 Heidelberg, Germany; andDepartment of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Neurology and Neurological Sciences,Neurosurgery.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Departments of Chemical and Systems Biology,Developmental Biology, and jameschen@stanford.edu.
authors.forename: James K
authors.initials: JK
authors.lastname: Chen
mesh_terms: D000818:Animals; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D020690:GTPase-Activating Proteins; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1