The G protein Gαs acts as a tumor suppressor in sonic hedgehog signaling-driven tumorigenesis

Rohit Rao, Ralph Salloum, Mei Xin, Q. Richard Lu

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1325-1330
Number of pages6
JournalCell Cycle
Volume15
Issue number10
DOIs
Publication statusPublished - May 18 2016

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Keywords

  • Basal cell carcinoma
  • cAMP-dependent PKA
  • G-protein
  • GNAS
  • GPCRs
  • Hedgehog signaling
  • Hippo signaling
  • medulloblastoma
  • Stem cells

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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