环腺苷酸依赖的蛋白激酶 A 通过稳定仅含 BH3 结构域的蛋白 Bim 来调节细胞凋亡。
Cyclic-AMP-dependent protein kinase A regulates apoptosis by stabilizing the BH3-only protein Bim.
机构信息
Department of Biochemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, Victoria 3086, Australia.
出版信息
EMBO Rep. 2011 Jan;12(1):77-83. doi: 10.1038/embor.2010.190. Epub 2010 Dec 10.
Abstract
The proapoptotic Bcl2 homology domain 3(BH3)-only protein Bim is controlled by stringent post-translational regulation, predominantly through alterations in phosphorylation status. To identify new kinases involved in its regulation, we carried out a yeast two-hybrid screen using a non-spliceable variant of the predominant isoform--Bim(EL)--as the bait and identified the regulatory subunit of cyclic-AMP-dependent protein kinase A--PRKAR1A--as an interacting partner. We also show that protein kinase A (PKA) is a Bim(EL) isoform-specific kinase that promotes its stabilization. Inhibition of PKA or mutation of the PKA phosphorylation site within Bim(EL) resulted in its accelerated proteasome-dependent degradation. These results might have implications for human diseases that are characterized by abnormally increased PKA activity, such as the Carney complex and dilated cardiomyopathy.
摘要
促凋亡 Bcl-2 同源结构域 3（BH3）-仅有蛋白 Bim 受到严格的翻译后调控，主要通过磷酸化状态的改变来调控。为了鉴定参与其调控的新激酶，我们使用主要同种型（Bim(EL)）的不可剪接变体作为诱饵进行酵母双杂交筛选，鉴定出环磷酸腺苷依赖性蛋白激酶 A 的调节亚基-PRKAR1A-作为相互作用伙伴。我们还表明，蛋白激酶 A（PKA）是一种 Bim(EL) 同种型特异性激酶，可促进其稳定。PKA 的抑制或 Bim(EL) 内 PKA 磷酸化位点的突变导致其加速蛋白酶体依赖性降解。这些结果可能对 Carney 综合征和扩张型心肌病等以 PKA 活性异常增加为特征的人类疾病具有重要意义。
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