title: An essential role for Gα(i2) in Smoothened-stimulated epithelial cell proliferation in the mammary gland.
abstract: Hedgehog (Hh) signaling is critical for organogenesis, tissue homeostasis, and stem cell maintenance. The gene encoding Smoothened (SMO), the primary effector of Hh signaling, is expressed aberrantly in human breast cancer, as well as in other cancers. In mice that express a constitutively active form of SMO that does not require Hh stimulation in mammary glands, the cells near the transgenic cells proliferate and participate in hyperplasia formation. Although SMO is a seven-transmembrane receptor like G protein-coupled receptors (GPCRs), SMO-mediated activation of the Gli family of transcription factors is not known to involve G proteins. However, data from Drosophila and mammalian cell lines indicate that SMO functions as a GPCR that couples to heterotrimeric G proteins of the pertussis toxin (PTX)-sensitive Gαi class. Using genetically modified mice, we demonstrated that SMO signaling through G proteins occurred in the mammary gland in vivo. SMO-induced stimulation of proliferation was PTX-sensitive and required Gαi2, but not Gαi1, Gαi3, or activation of Gli1 or Gli2. Our findings show that activated SMO functions as a GPCR to stimulate proliferation in vivo, a finding that may have clinical importance because most SMO-targeted agents have been selected based largely on their ability to block Gli-mediated transcription.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Hugo
authors.initials: H
authors.lastname: Villanueva
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Adriana P
authors.initials: AP
authors.lastname: Visbal
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Nadine F
authors.initials: NF
authors.lastname: Obeid
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Andrew Q
authors.initials: AQ
authors.lastname: Ta
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Adeel A
authors.initials: AA
authors.lastname: Faruki
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Meng-Fen
authors.initials: MF
authors.lastname: Wu
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.affiliation: Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Plummer
authors.affiliation: Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA. mtlewis@bcm.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lewis
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D004330:Drosophila; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072086:Smoothened Receptor
chemical_list: D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D051960:GTP-Binding Protein alpha Subunit, Gi2; C498016:Gnai2 protein, mouse