title: Fatty acylated caveolin-2 is a substrate of insulin receptor tyrosine kinase for insulin receptor substrate-1-directed signaling activation.
abstract: 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.
authors: Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors: Hayeong
authors: H
authors: Kwon
authors: Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors: Jaewoong
authors: J
authors: Lee
authors: Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors: Kyuho
authors: K
authors: Jeong
authors: Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors: Donghwan
authors: D
authors: Jang
authors: Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Republic of Korea. Electronic address: ybpak@gnu.ac.kr.
authors: Yunbae
authors: Y
authors: Pak
mesh_terms: D000215:Acylation / Q000187:drug effects; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D051243:Caveolin 2 / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D054878:Lipoylation / Q000187:drug effects; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D051243:Caveolin 2; D005227:Fatty Acids; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D008934:Mitogens; D019000:Phosphotyrosine; C410467:insulin receptor tyrosine kinase; D011505:Protein-Tyrosine Kinases; D003545:Cysteine
keywords: Caveolin-2; Cell proliferation and survival; Fatty acylation; Glucose uptake; Insulin receptor substrate-1; Insulin receptor tyrosine kinase