title: The alpha subunit of the G protein G13 regulates activity of one or more Gli transcription factors independently of smoothened.
abstract: Smoothened (Smo) is a seven-transmembrane (7-TM) receptor that is essential to most actions of the Hedgehog family of morphogens. We found previously that Smo couples to members of the G(i) family of heterotrimeric G proteins, which in some cases are integral although alone insufficient in the activation of Gli transcription factors through Hedgehog signaling. In response to a report that the G(12/13) family is relevant to Hedgehog signaling as well, we re-evaluated the coupling of Smo to one member of this family, G(13), and investigated the capacity of this and other G proteins to activate one or more of forms of Gli. We found no evidence that Smo couples directly to G(13). We found nonetheless that Gα(13) and to some extent Gα(q) and Gα(12) are able to effect activation of Gli(s). This capacity is realized in some cells, e.g. C3H10T1/2, MC3T3, and pancreatic cancer cells, but not all cells. The mechanism employed is distinct from that achieved through canonical Hedgehog signaling, as the activation does not involve autocrine signaling or in any other way require active Smo and does not necessarily involve enhanced transcription of Gli1. The activation by Gα(13) can be replicated through a G(q)/G(12/13)-coupled receptor, CCK(A), and is attenuated by inhibitors of p38 mitogen-activated protein kinase and Tec tyrosine kinases. We posit that G proteins, and perhaps G(13) in particular, provide access to Gli that is independent of Smo and that they thus establish a basis for control of at least some forms of Gli-mediated transcription apart from Hedgehogs.
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Douglas
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Heim
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Feng
authors.initials: F
authors.lastname: Shen
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.affiliation: Department of Biochemistry and Molecular Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Riobo
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernández-Zapico
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104. Electronic address: manning@mail.med.upenn.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Manning
mesh_terms: D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008954:Models, Biological; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D044365:GTP-Binding Protein alpha Subunits, G12-G13