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 language | English (US) |
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Pages (from-to) | 1325-1330 |
Number of pages | 6 |
Journal | Cell Cycle |
Volume | 15 |
Issue number | 10 |
DOIs | |
State | Published - May 18 2016 |
Keywords
- Basal cell carcinoma
- G-protein
- GNAS
- GPCRs
- Gα
- Hedgehog signaling
- Hippo signaling
- Stem cells
- cAMP-dependent PKA
- medulloblastoma
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology
- Cell Biology