The Subunit of the G Protein G13 Regulates Activity of One or More Gli Transcription Factors Independently of Smoothened

Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2011; 286(35):30714-22. DOI: 10.1074/jbc.M111.219279
Source: PubMed


Smoothened (Smo) is a seven-transmembrane (7-TM) receptor that is essential to most actions of the Hedgehog family of morphogens.
We found previously that Smo couples to members of the Gi family of heterotrimeric G proteins, which in some cases are integral although alone insufficient in the activation of Gli
transcription factors through Hedgehog signaling. In response to a report that the G12/13 family is relevant to Hedgehog signaling as well, we re-evaluated the coupling of Smo to one member of this family, G13, and investigated the capacity of this and other G proteins to activate one or more of forms of Gli. We found no evidence
that Smo couples directly to G13. We found nonetheless that Gα13 and to some extent Gαq and Gα12 are able to effect activation of Gli(s). This capacity is realized in some cells, e.g. C3H10T1/2, MC3T3, and pancreatic cancer cells, but not all cells. The mechanism employed is distinct from that achieved through
canonical Hedgehog signaling, as the activation does not involve autocrine signaling or in any other way require active Smo
and does not necessarily involve enhanced transcription of Gli1. The activation by Gα13 can be replicated through a Gq/G12/13-coupled receptor, CCKA, and is attenuated by inhibitors of p38 mitogen-activated protein kinase and Tec tyrosine kinases. We posit that G proteins,
and perhaps G13 in particular, provide access to Gli that is independent of Smo and that they thus establish a basis for control of at least
some forms of Gli-mediated transcription apart from Hedgehogs.

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Available from: Natalia A Riobo-Del Galdo, Mar 31, 2015
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