N-myristoylation regulates insulin-induced phosphorylation and ubiquitination of Caveolin-2 for insulin signaling

Kwon, Hayeong; Choi, Moonjeong; Ahn, Yujin; Pak, Yunbae

N-myristoylation regulates insulin-induced phosphorylation and ubiquitination of Caveolin-2 for insulin signaling

2020

Kwon, Hayeong | Choi, Moonjeong | Ahn, Yujin | Pak, Yunbae

N-myristoylation is a ubiquitous protein lipidation in eukaryotes, but regulatory roles for myristoylation on proteins still remain to be explored. Here, we show that N-myristoylation of Caveolin-2 (Cav-2) controls insulin signaling. Alternative translation initiation (ATI)-yielded truncated form of non-N-myristoylable Cav-2β and various conditional Cav-2 mutants were compared to full-length form of N-myristoylable Cav-2α. Insulin induced insulin receptor (IR) tyrosine kinase-catalyzed Tyr-19 phosphorylation of N-myristoylable M14A Cav-2 and triggered activation of IR signaling cascade. In contrast, insulin induced ubiquitination of non-N-myristoylable M1A and G2A Cav-2 to facilitate protein-tyrosine phosphatase 1B interaction with IR which desensitized IR signaling through internalization. Metabolic labeling and click chemistry showed palmitoylation of M14A but not M1A and G2A Cav-2. Insulin did not induce phosphorylation of M1A and G2A Cav-2 and Cav-2β. Like Cav-2α, G2A Cav-2 and Cav-2β formed large homo-oligomers localized in lipid rafts. These findings show Cav-2 N-myristoylation plays a crucial role to coordinate its phosphorylation, palmitoylation, and ubiquitination to control insulin signaling.

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