title: Sonic Hedgehog activates the GTPases Rac1 and RhoA in a Gli-independent manner through coupling of smoothened to Gi proteins.
abstract: The vertebrate Hedgehog (Hh) pathway has essential functions during development and tissue homeostasis in normal physiology, and its dysregulation is a common theme in cancer. The Hh ligands (Sonic Hh, Indian Hh, and Desert Hh) bind to the receptors Patched1 and Patched2, resulting in inhibition of their repressive effect on Smoothened (Smo). Smo is a seven-transmembrane protein, which was only recently shown to function as a G protein-coupled receptor (GPCR) with specificity toward the heterotrimeric guanine nucleotide-binding protein G(i). In addition to activating G(i), Smo signals through its C-terminal tail to inhibit Suppressor of Fused, resulting in stabilization and activation of the Gli family of transcription factors, which execute a transcriptional response to so-called "canonical Hh signaling." In this Presentation, we illustrate two outcomes of Hh signaling that are independent of Gli transcriptional activity and, thus, are defined as "noncanonical." One outcome is dependent on Smo coupling to G(i) proteins and exerts changes to the actin cytoskeleton through stimulation of the small guanosine triphosphatases (GTPases) RhoA and Rac1. These cytoskeletal changes promote migration in fibroblasts and tubulogenesis in endothelial cells. Signaling through the other noncanonical Hh pathway is independent of Smo and inhibits Patched1-induced cell death.
authors: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Ariel H
authors: AH
authors: Polizio
authors: Pilar
authors: P
authors: Chinchilla
authors: Xiaolen
authors: X
authors: Chen
authors: David R
authors: DR
authors: Manning
authors: Natalia A
authors: NA
authors: Riobo
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000072082:Patched-2 Receptor; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; C000606238:PTCH2 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000072082:Patched-2 Receptor; C107953:RAC1 protein, human; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; C509239:SHH protein, human; C491023:SMO protein, human; C490764:SUFU protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C066737:RHOA protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein