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The Regulator of G Protein Signaling Domain of Axin Selectively Interacts with G₁₂ but Not G₁₃

Departments 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 G₁₃ or with several other heterotrimeric G proteins. Axin preferentially binds the activated form of G₁₂, a behavior consistent with other RGS proteins. However, unlike other RGS proteins, that of axin (axinRGS) does not affect intrinsic GTP hydrolysis by G₁₂. Despite its inability to act as a GTPase-activating protein, we demonstrate that in cells, axinRGS can compete for G₁₂ 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 G₁₂-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 G₁₂-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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