Role of Cbl in signaling from receptor tyrosine kinases

Cbl 在受体酪氨酸激酶信号传导中的作用

• 批准号: 11671088
• 负责人: OKABAYASHI Yoshinori
• 金额: $ 2.3万
• 依托单位: Kobe University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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/grant/KAKENHI-PROJECT-11671088/
• 关键词: Cbl; EGF receptor; PI3 kinase; Akt; MAP kinase; apoptosis; PI-3キナーゼ; apoptosis

In the present study, I investigated the role of Cbl and Cbl- phosphoinisitide (PI) 3 kinase complex in signaling from receptor tyrosine kinases, especially epidermal growth factor (EGF) receptors. For this end, I constructed adenoviral vectors carrying wild-type and mutant Cbl in which the binding sites of 85-kDa regulatory subunit of PI3 kinase were disrupted. The major binding site for PI3 kinase within Cbl was tyrosine at 731, which represents Tyr-Xaa-Xaa-Met motif. When wild-type Cbl was overexpressed in Cos, A431, and A549 cells, EGF receptor autophosphorylation, MAP kinase activation, and Akt activation in response to EGF stimulation was markedly reduced. Inhibition by mutant Cbl was similar to that by wild-type Cbl. Cbl abolished the protective effect of EGF on UV-induced apoptosis in Cos and A431 cells. Thus, Cbl inhibits EGF receptor kinase and PI3 kinase associated with Cbl does not have major role in mitogenic signaling from EGF receptors.

在本研究中，我研究了CBL和CBL-磷酸依酶（PI）3激酶复合物在受体酪氨酸激酶（尤其是表皮生长因子（EGF）受体的信号传导中）的作用。为此，我构建了带有野生型和突变型CBL的腺病毒载体，其中pi3激酶的85 kDa调节亚基的结合位点被中断。 CBL内PI3激酶的主要结合位点是731的酪氨酸，代表Tyr-XAA-XAA-MET基序。当野生型CBL在COS，A431和A549细胞中过表达时，EGF受体自磷酸化，MAP激酶激活和响应于EGF刺激的AKT激活显着降低。突变CBL抑制与野生型CBL相似。 CBL废除了EGF对COS和A431细胞中紫外线诱导的凋亡的保护作用。因此，CBL抑制与CBL相关的EGF受体激酶和PI3激酶在EGF受体的有丝分裂信号传导中没有主要作用。