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An essential role for Gαi2 in Smoothened-stimulated epithelial cell proliferation in the mammary gland

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Sci. Signal.  15 Sep 2015:
Vol. 8, Issue 394, pp. ra92
DOI: 10.1126/scisignal.aaa7355

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Smoothened signals through G proteins

The Hedgehog signaling pathway promotes the expression of genes that are critical during development through regulation of the Gli family of transcription factors. Because this pathway is subverted by cancer cells, and because the gene encoding the Hedgehog effector Smoothened (SMO) is aberrantly expressed in some types of breast cancers, various chemotherapeutics have been developed to target SMO. Villanueva et al. (see also the Focus by Ogden) showed that SMO promoted cell proliferation in the mammary glands of mice through the G protein Gαi2, rather than through Gli-mediated changes in gene expression. These results confirm that SMO can act as a G protein–coupled receptor in mammals and suggest that SMO-targeting drugs should also be screened for their ability to inhibit Gαi2 activation.


Hedgehog (Hh) signaling is critical for organogenesis, tissue homeostasis, and stem cell maintenance. The gene encoding Smoothened (SMO), the primary effector of Hh signaling, is expressed aberrantly in human breast cancer, as well as in other cancers. In mice that express a constitutively active form of SMO that does not require Hh stimulation in mammary glands, the cells near the transgenic cells proliferate and participate in hyperplasia formation. Although SMO is a seven-transmembrane receptor like G protein–coupled receptors (GPCRs), SMO-mediated activation of the Gli family of transcription factors is not known to involve G proteins. However, data from Drosophila and mammalian cell lines indicate that SMO functions as a GPCR that couples to heterotrimeric G proteins of the pertussis toxin (PTX)–sensitive Gαi class. Using genetically modified mice, we demonstrated that SMO signaling through G proteins occurred in the mammary gland in vivo. SMO-induced stimulation of proliferation was PTX-sensitive and required Gαi2, but not Gαi1, Gαi3, or activation of Gli1 or Gli2. Our findings show that activated SMO functions as a GPCR to stimulate proliferation in vivo, a finding that may have clinical importance because most SMO-targeted agents have been selected based largely on their ability to block Gli-mediated transcription.

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