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The proto-oncogene SET interacts with muscarinic receptors and attenuates receptor signaling.

ABSTRACT: G protein-coupled receptors mediate cell responses to extracellular stimuli and likely function in the context of a larger signal transduction complex. Utilizing the third intracellular loop of a G protein-coupled receptor in glutathione S-transferase pulldown assays from rat brain lysates coupled with high sensitivity detection methods and subsequent functional studies, we report the identification of SET as a regulator of muscarinic receptor signaling. SET is a putative oncogene reported to inhibit protein phosphatase 2A and regulate gene transcription. SET binds the carboxyl region of the M3-muscarinic receptor i3 loop, and endogenous SET co-immunoprecipitates with intact M3 muscarinic receptor expressed in cells. Small interfering RNA knockdown of endogenous SET in Chinese hamster ovary cells stably expressing the M3 muscarinic receptor augmented receptor-mediated mobilization of intracellular calcium by approximately 35% with no change in agonist EC(50), indicating that interaction of SET with the M3 muscarinic receptor reduces its signaling capacity. SET knockdown had no effect on the mobilization of intracellular calcium by the P2-purinergic receptor, ionomycin, or a direct activator of phospholipase C, indicating a specific regulation of M3 muscarinic receptor signaling. These data provide expanded functionality for SET and a previously unrecognized mechanism for regulation of GPCR signaling capacity.

SUBMITTER: Simon V

PROVIDER: S-EPMC2596874 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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The proto-oncogene SET interacts with muscarinic receptors and attenuates receptor signaling.

Simon Violaine V Guidry Jessie J Gettys Thomas W TW Tobin Andrew B AB Lanier Stephen M SM

The Journal of biological chemistry 20061025 52

G protein-coupled receptors mediate cell responses to extracellular stimuli and likely function in the context of a larger signal transduction complex. Utilizing the third intracellular loop of a G protein-coupled receptor in glutathione S-transferase pulldown assays from rat brain lysates coupled with high sensitivity detection methods and subsequent functional studies, we report the identification of SET as a regulator of muscarinic receptor signaling. SET is a putative oncogene reported to in ...[more]

PMID: 17065150

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The proto-oncogene SET interacts with muscarinic receptors and attenuates receptor signaling.

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The proto-oncogene SET interacts with muscarinic receptors and attenuates receptor signaling.

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