New perspectives of the molecular mechanisms to potentiate IGF signals

增强IGF信号分子机制的新视角

• 批准号: 11460126
• 负责人: TAKAHASHI Shin-ichiro
• 金额: $ 3.97万
• 依托单位: THE UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11460126/
• 关键词: Insulin-like growth factors; Tropic hormone; cAMP; Signal closstalk; Intracellular signaling; Tyrosine phosphorylation; Proliferation; Tyrosine kinase; クロストーク

In many cell types IGF-I has been shown to possess a variety of bioactivities. Despite the profuseness and diversity of these effects of IGFs, the in vitro biological effects of IGFs are relatively weak and often are not demonstrable except in the presence of other hormones or growth factors. These findings suggest that IGFs act as permissive factors to augment the signals or other factors. We have shown that in FRTL-5, a thyroid follicular cell line, TSH and IGF-I stimulate cell growth synergistically and cAMP pretreatment is essential for the potentiation of IGF-I-dependent DNA synthesis. In this cell line, cAMP pretreatment caused an increase in tyrosine kinase activity and tyrosine phosphorylation of intracellular proteins such as a 125-kDa protein (p125), which was well correlated with a cAMP-priming effect on potentiation of DNA synthesis induced by IGF-I.We recently found that the phosphotyrosyl p125 bound to a PI-3 kinase p85 regulatory subunit, and LY294002 (a PI-3 kinase inhi … More bitor) blocked the cAMP-priming effect. Taken together with the data that tyrosine kinase and PI-3 kinase activities are necessary for cAMP-dependent increases in Gl cyclins, our results suggest that CAMP stimulus recruit the quiescent cells into the cell cycle through cAMP-induced changes of tyrosine phosphorylation. On the other hand, we demonstrated that cAMP pretreatment potentiated IRS-2 and Shc tyrosine phosphorylation induced by IGF-I, although pretreatment with cAMP did not affect autophosphorylation of the IGF-I receptor. cAMP pretreatment increased Grb2 binding to IRS-2 and Shc, and MAP kinase activation induced by IGF-I was also enhanced by cAMP stimulus. Furthermore, cAMP pretreatment increased IRS-2 association with the PI-3 kinase p85 subunit, and IGF-I-induced PI-3 kinase activity bound to IRS-2 was enhanced by cAMP pretreatment. Finally, the presence of PD98059 (a MEK inhibitor) or LY294002 during IGF-I treatment abolished the cAMP-dependent augmentation of IGF-I dependent DNA synthesis. These results suggest that cAMP stimulus amplifies the IGF-I signals through cAMP-dependent potentiation of tyrosine phosphorylation of IGF-I receptor substrates. In conclusion, interaction between tropic hormone-dependent and IGF-I-dependent pathways leads to an augmentation of cell proliferation through the cAMP-dependent process of priming the cells to respond to IGF-I and amplification of IGF-I mitogenic activities. Less

在许多细胞类型中，IGF-I已被证明具有多种生物活性。尽管IGFs的这些作用的丰富性和多样性，但IGFs的体外生物学作用相对较弱，并且通常除非在其他激素或生长因子存在下才能证明。这些发现表明，IGFs作为许可因素，以增加信号或其他因素。我们已经表明，在FRTL-5，甲状腺滤泡细胞系，促甲状腺激素和IGF-I刺激细胞生长协同和cAMP预处理是必不可少的IGF-I依赖的DNA合成的增强。在该细胞系中，cAMP预处理导致酪氨酸激酶活性增加和细胞内蛋白质（例如125-kDa蛋白质（p125））的酪氨酸磷酸化，这与cAMP对IGF-I诱导的DNA合成增强的引发作用密切相关。我们最近发现磷酸酪氨酰p125与PI-3激酶p85调节亚基结合，和LY 294002（一种PI-3激酶抑制剂）。 ...更多信息 bitor）阻断cAMP启动效应。结合酪氨酸激酶和PI-3激酶活性是cAMP依赖性G1期细胞周期蛋白增加所必需的数据，我们的结果表明，cAMP刺激通过cAMP诱导的酪氨酸磷酸化变化将静止细胞招募到细胞周期中。另一方面，我们证明，cAMP预处理增强胰岛素样生长因子-I诱导的IRS-2和Shc酪氨酸磷酸化，虽然用cAMP预处理不影响IGF-I受体的自磷酸化。cAMP预处理增加了Grb 2与IRS-2和Shc的结合，cAMP刺激也增强了IGF-I诱导的MAP激酶激活。此外，cAMP预处理增加了IRS-2与PI-3激酶p85亚基的结合，cAMP预处理增强了IGF-1诱导的PI-3激酶与IRS-2结合的活性。最后，在IGF-I处理期间PD 98059（MEK抑制剂）或LY 294002的存在消除了cAMP依赖性的IGF-I依赖性DNA合成的增加。这些结果表明cAMP刺激通过cAMP依赖性增强IGF-I受体底物的酪氨酸磷酸化来放大IGF-I信号。总之，嗜热蛋白依赖性途径和IGF-I依赖性途径之间的相互作用导致通过cAMP依赖性过程引发细胞对IGF-I的应答和IGF-I促有丝分裂活性的扩增来增强细胞增殖。少

项目成果

肥塚直美 他: "IGF研究の進歩と展開-ブライトンからのメッセージ"ホルモンと臨床. 48. 103-107 (2000)

Naomi Kizuka 等人：“IGF 研究的进展和发展 - 来自布莱顿的消息”激素和临床研究 48. 103-107 (2000)。

根建拓 他: "血中のエンドクリン型インスリン様成長因子は生後の成長に必要か?"内分泌・糖尿病科. 11. 378-387 (2000)

Taku Neken 等人：“血液中的内分泌型胰岛素样生长因子对于产后生长是必需的吗？”11. 378-387 (2000)。

Ariga M, Nedachi T, Akahori M, Sakamoto H, Ito Y, Hakuno F, Takahashi S-I: "Signaling pathways of insulin-like growth factor-I that are augmented by cAMP in FRTL-5 cells."Biochem.J.. 348. 409-416 (2000)

Ariga M、Nedachi T、Akahori M、Sakamoto H、Ito Y、Hakuno F、Takahashi S-I：“FRTL-5 细胞中 cAMP 增强胰岛素样生长因子-I 的信号通路。”Biochem.J.. 348

Oki N et al.: "Short-time feedback regulation of cAMP in FRTL-5 thyroid cells : Role of PDE4D3 phosphodiesterase activation"J.Biol.Chem. 275. 10831-10837 (2000)

Oki N 等人：“FRTL-5 甲状腺细胞中 cAMP 的短时反馈调节：PDE4D3 磷酸二酯酶激活的作用”J.Biol.Chem。

伯野史彦 他: "インスリン様成長因子の遺伝子を過剰発現あるいは欠損させたらどうなるか"ホルモンと臨床. 47. 491-505 (1999)

Fumihiko Hakuno 等人：“如果胰岛素样生长因子基因过度表达或删除会发生什么？” 47. 491-505 (1999)。