Stearic acid blunts growth-factor signaling via oleoylation of GNAI proteins.

ABSTRACT

Covalent attachment of C160 to proteins (palmitoylation) regulates protein function. Proteins are also S-acylated by other fatty acids including C180. Whether protein acylation with different fatty acids has different functional outcomes is not well studied. We show here that C180 (stearate) and C181 (oleate) compete with C160 to S-acylate Cys3 of GNAI proteins. C180 becomes desaturated so that C180 and C181 both cause S-oleoylation of GNAI. Exposure of cells to C160 or C180 shifts GNAI acylation towards palmitoylation or oleoylation, respectively. Oleoylation causes GNAI proteins to shift out of cell membrane detergent-resistant fractions where they potentiate EGFR signaling. Consequently, exposure of cells to C180 reduces recruitment of Gab1 to EGFR and reduces AKT activation. This provides a molecular mechanism for the anti-tumor effects of C180, uncovers a mechanistic link how metabolites affect cell signaling, and provides evidence that the identity of the fatty acid acylating a protein can have functional consequences.