Fatty acylated caveolin-2 is a substrate of insulin receptor tyrosine kinase for insulin receptor substrate-1-directed signaling activation.

Here, we demonstrate that insulin receptor (IR) tyrosine kinase catalyzes Tyr-19 and Tyr-27 phosphorylation of caveolin-2 (cav-2), leading to stimulation of signaling proteins downstream of IR, and that the catalysis is dependent on fatty acylation status of cav-2, promoting its interaction with IR. Cav-2 is myristoylated at Gly-2 and palmitoylated ...
at Cys-109, Cys-122, and Cys-145. The fatty acylation deficient mutants are unable to localize in the plasma membrane and not phosphorylated by IR tyrosine kinase. IR interacts with the C-terminal domain of cav-2 containing the cysteines for palmitoylation. IR mutants, Y999F and K1057A, but not W1220S, fail interaction with cav-2. Insulin receptor substrate-1 (IRS-1) is recruited to interact with the IR-catalyzed phospho-tyrosine cav-2, which facilitates IRS-1 association with and activation by IR to initiate IRS-1-mediated downstream signaling. Cav-2 fatty acylation and tyrosine phosphorylation are necessary for the IRS-1-dependent PI3K-Akt and ERK activations responsible for glucose uptake and cell survival and proliferation. In conclusion, fatty acylated cav-2 is a new substrate of IR tyrosine kinase, and the fatty acylation and phosphorylation of cav-2 present novel mechanisms by which insulin signaling is activated.
Mesh Terms:
Acylation, Amino Acid Motifs, Amino Acid Sequence, Animals, Biocatalysis, Caveolin 2, Cell Line, Cysteine, Fatty Acids, Gene Knockdown Techniques, Humans, Insulin, Insulin Receptor Substrate Proteins, Intracellular Space, Lipoylation, Mice, Mitogens, Models, Biological, Molecular Sequence Data, Phosphorylation, Phosphotyrosine, Protein Binding, Protein Transport, Protein-Tyrosine Kinases, Rats, Signal Transduction, Substrate Specificity
Biochim. Biophys. Acta
Date: May. 01, 2015
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