徳島大学 教育・研究者情報データベース(EDB)

1. (英) Ogihara T

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2. (英) Isobe T

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3. (英) Ichimura T

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4. (英) Taoka M

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5. 船木 真理

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6. (英) Sakoda H

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7. (英) Onishi Y

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8. (英) Inukai K

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9. (英) Anai M

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10. (英) Fukushima Y

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11. (英) Kikuchi M

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12. (英) Yazaki Y

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13. (英) Oka Y

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14. (英) Asano T

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(英) 14-3-3 protein binds to insulin receptor substrate-1, one of the binding sites of which is in the phosphotyrosine binding domain.

(英) Insulin binding to its receptor induces the phosphorylation of cytosolic substrates, insulin receptor substrate (IRS)-1 and IRS-2, which associate with several Src homology-2 domain-containing proteins. To identify unique IRS-1-binding proteins, we screened a human heart cDNA library with 32P-labeled recombinant IRS-1 and obtained two isoforms (epsilon and zeta) of the 14-3-3 protein family. 14-3-3 protein has been shown to associate with IRS-1 in L6 myotubes, HepG2 hepatoma cells, Chinese hamster ovary cells, and bovine brain tissue. IRS-2, a protein structurally similar to IRS-1, was also shown to form a complex with 14-3-3 protein using a baculovirus expression system. The amount of 14-3-3 protein associated with IRS-1 was not affected by insulin stimulation but was increased significantly by treatment with okadaic acid, a potent serine/threonine phosphatase inhibitor. Peptide inhibition experiments using phosphoserine-containing peptides of IRS-1 revealed that IRS-1 contains three putative binding sites for 14-3-3 protein (Ser-270, Ser-374, and Ser-641). Among these three, the motif around Ser-270 is located in the phosphotyrosine binding domain of IRS-1, which is responsible for the interaction with the insulin receptor. Indeed, a truncated mutant of IRS-1 consisting of only the phosphotyrosine binding domain retained the capacity to bind to 14-3-3 protein in vivo. Finally, the effect of 14-3-3 protein binding on the insulin-induced phosphorylation of IRS-1 was investigated. Phosphoamino acid analysis revealed that IRS-1 coimmunoprecipitated with anti-14-3-3 antibody to be weakly phosphorylated after insulin stimulation, on tyrosine as well as serine residues, compared with IRS-1 immunoprecipitated with anti-IRS-1 antibody. Thus, the association with 14-3-3 protein may play a role in the regulation of insulin sensitivity by interrupting the association between the insulin receptor and IRS-1.

1. (英) 14-3-3 Proteins
2. アデノシン三リン酸(adenosine triphosphate)
3. (英) Amino Acid Sequence
4. (英) Animals
5. (英) Binding Sites
6. 脳(brain)
7. (英) CHO Cells
8. (英) Carcinoma, Hepatocellular
9. (英) Cattle
10. (英) Cell Line
11. (英) Cricetinae
12. (英) Gene Library
13. (英) Humans
14. インスリン(insulin)
15. (英) Insulin Receptor Substrate Proteins
16. (英) Intracellular Signaling Peptides and Proteins
17. (英) Liver Neoplasms
18. (英) Mice
19. (英) Molecular Sequence Data
20. 心筋(myocardium)
21. (英) Okadaic Acid
22. (英) Phosphoproteins
23. (英) Phosphorus Radioisotopes
24. (英) Phosphotyrosine
25. (英) Protein Biosynthesis
26. (英) Proteins
27. (英) Rats
28. (英) Receptor, Insulin
29. (英) Recombinant Proteins
30. (英) Sequence Alignment
31. (英) Sequence Homology, Amino Acid
32. (英) Spodoptera
33. (英) Transfection
34. (英) Tumor Cells, Cultured
35. (英) Tyrosine 3-Monooxygenase

1. (英) PublicationType: Journal Article

2. (英) PublicationType: Research Support, Non-U.S. Gov't