title: The G protein Gαs acts as a tumor suppressor in sonic hedgehog signaling-driven tumorigenesis.
abstract: G protein-coupled receptors (GPCRs) are critical players in tumor growth and progression. The redundant roles of GPCRs in tumor development confound effective treatment; therefore, targeting a single common signaling component downstream of these receptors may be efficacious. GPCRs transmit signals through heterotrimeric G proteins composed of Gα and Gβγ subunits. Hyperactive Gαs signaling can mediate tumor progression in some tissues; however, recent work in medulloblastoma and basal cell carcinoma revealed that Gαs can also function as a tumor suppressor in neoplasms derived from ectoderm cells including neural and epidermal stem/progenitor cells. In these stem-cell compartments, signaling through Gαs suppresses self-renewal by inhibiting the Sonic Hedgehog (SHH) and Hippo pathways. The loss of GNAS, which encodes Gαs, leads to activation of these pathways, over-proliferation of progenitor cells, and tumor formation. Gαs activates the cAMP-dependent protein kinase A (PKA) signaling pathway and inhibits activation of SHH effectors Smoothened-Gli. In addition, Gαs-cAMP-PKA activation negatively regulates the Hippo pathway by blocking the NF2-LATS1/2-Yap signaling. In this review, we will address the novel function of the signaling network regulated by Gαs in suppression of SHH-driven tumorigenesis and the therapeutic approaches that can be envisioned to harness this pathway to inhibit tumor growth and progression.
authors.affiliation: a University of Cincinnati Medical Scientist Training Program , Cincinnati , OH , USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Rao
authors.affiliation: b Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center , Cincinnati , OH , USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Salloum
authors.affiliation: b Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center , Cincinnati , OH , USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xin
authors.affiliation: b Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center , Cincinnati , OH , USA.
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D002528:Cerebellar Neoplasms / Q000378:metabolism / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D025521:Tumor Suppressor Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: Basal cell carcinoma; G-protein; GNAS; GPCRs; Gαs; Hedgehog signaling; Hippo signaling; Stem cells; cAMP-dependent PKA; medulloblastoma