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Palmitoylation and Plasma Membrane Targeting of RGS7 Are Promoted by _o

Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania

Regulator of G protein signaling (RGS) proteins modulate G protein signaling by acting as GTPase-activating proteins for G protein -subunits. RGS7 belongs to a subfamily of RGS proteins that exist as dimers with the G protein ₅-subunit. In this report, we addressed the mechanisms of plasma membrane localization of ₅RGS7. When expressed in human embryonic kidney 293 cells, ₅RGS7 was found to be cytoplasmic and soluble. Expression of _o promoted a strong redistribution of ₅RGS7 to the plasma membrane. Expression of _q, however, failed to affect the subcellular localization of ₅RGS7. The constitutively active mutant _oR179C, like wild-type _o, strongly recruited ₅RGS7 to plasma membranes; however, inactive _oG204A, RGS-insensitive _oG184S, and lipidation-deficient _oG2A were all defective in the ability to promote plasma membrane localization of ₅RGS7. In addition, palmitoylation of RGS7 was demonstrated, and palmitoylation required expression of _o or _oR179C. To examine potential palmitoylation sites of RGS7, several cysteines were substituted with serines. ₅RGS7C133S failed to localize to plasma membranes when coexpressed with _o, suggesting cysteine 133 of RGS7 as a putative palmitoylation site. Finally, deletion of amino acids 76 to 128 of RGS7, which includes part of the disheveled, EGL-10, pleckstrin (DEP) domain, prevented _o-mediated plasma membrane recruitment of ₅RGS7. These findings are the first to demonstrate G-regulated plasma membrane localization and palmitoylation of ₅RGS7 and suggest that membrane targeting of ₅RGS7 is a complex process requiring at least RGS domain-mediated interaction with _o and RGS7 palmitoylation.

Received for publication June 1, 2004.

Accepted for publication October 19, 2004.

Address correspondence to: Philip B. Wedegaertner, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, 839 BLSB, Philadelphia, PA 19107. E-mail: p_wedegaertner{at}mail.jci.tju.edu

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