GTPase的RAS和RHO家族直接调节不同的酸酸3-激酶异型
Ralph Fritsch1, Inge de Krijger, Kornelia Fritsch
1Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Cell
|May 28, 2013
概括
拉斯蛋白激活一些氨基酸3-激酶 (PI3Ks),但不是p110β. 相反,RHO GTPases RAC1和CDC42激活p110β,影响细胞信号和纤维化.
科学领域:
- 分子生物学分子生物学
- 细胞信号传递 细胞信号传递
- 癌症研究 癌症研究
背景情况:
- RAS蛋白通过它们的RAS结合域 (RBD) 激活特定的I型酸酸3-激酶 (PI3Ks),如p110α,p110γ和p110δ.
- PI3K的p110β异型参与G蛋白结合受体 (GPCR) 信号传递,PTEN损失癌症和血小板功能.
- 小GTPases对p110βPI3K异型的调节机制以前尚不清楚.
研究的目的:
- 为了研究氏酸 3-激酶 (PI3K) 的p110β异型的调节.
- 确定与p110β相互作用并激活的特定小GTPase.
- 阐明p110β调节在细胞过程 (如化学反应) 和肺纤维化等疾病模型中的作用.
主要方法:
- 使用生物化学测试研究了RAS和p110β之间的相互作用.
- 确定了RAC1和CDC42作为p110β的RBD的绑定伙伴.
- 利用带有p110β RBD突变的纤维细胞和小鼠模型来评估PI3K活性,化疗和肺纤维化.
- 研究了Dock180/Elmo1在调解GPCRs下游的RAC激活中的作用.
主要成果:
- 拉斯蛋白不与PI3K的p110β异型相互作用或激活.
- 小型GTPase的RHO亚家族成员RAC1和CDC42通过其RBD直接结合并激活p110β.
- 通过Dock180/Elmo1,GPCRs发出信号来激活RAC,然后RAC与纤维细胞中的p110β相互作用.
- 具有p110β RBD突变的小鼠表现出PI3K活性降低,化学反应缺陷,以及对实验性肺纤维化的耐药性.
结论:
- RAS和RHO家族GTPases不同调节不同的PI3K异型.
- RAC1和CDC42是p110β PI3K异型的直接激活剂.
- GPCRs下游的RAC激活在p110β介导的细胞功能和纤维性反应中起着至关重要的作用.
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