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Cell Cycle. 2016 May 18;15(10):1325-30. doi: 10.1080/15384101.2016.1164371.

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

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a University of Cincinnati Medical Scientist Training Program , Cincinnati , OH , USA.
b Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center , Cincinnati , OH , USA.


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.


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

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