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12 but Not G
13Departments of Pathology (L.N.S., T.A.F.) and Pharmacology and Cancer Biology (P.J.C.), Duke University Medical Center, Durham, North Carolina
Axin, a negative regulator of the Wnt signaling pathway, contains a canonical regulator of G protein signaling (RGS) core domain. Herein, we demonstrate both in vitro and in cells that this domain interacts with the
subunit of the heterotrimeric G protein G12 but not with the closely related G
13 or with several other heterotrimeric G proteins. Axin preferentially binds the activated form of G
12, a behavior consistent with other RGS proteins. However, unlike other RGS proteins, that of axin (axinRGS) does not affect intrinsic GTP hydrolysis by G
12. Despite its inability to act as a GTPase-activating protein, we demonstrate that in cells, axinRGS can compete for G
12 binding with the RGS domain of p115RhoGEF, a known G12-interacting protein that links G12 signaling to activation of the small G protein Rho. Moreover, ectopic expression of axinRGS specifically inhibits G
12-directed activation of the Rho pathway in MDA-MB 231 breast cancer cells. These findings establish that the RGS domain of axin is able to directly interact with the
subunit of heterotrimeric G protein G12 and provide a unique tool to interdict G
12-mediated signaling processes.
Address correspondence to: Timothy A. Fields, Department of Pathology, Duke University Medical Center, Box 3712, Durham, NC 27710. E-mail: taf1{at}duke.edu.
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