Signaling specificity in the Akt pathway in biology and disease.
Signaling specificity in the Akt pathway in biology and disease.
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DOI：
10.1016/j.jbior.2014.04.001
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发表时间：
2014-05
影响因子：
--
通讯作者：
Marmiroli, Sandra
中科院分区：
文献类型：
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作者：
Toker, Alex;Marmiroli, Sandra
Akt/PKB是一个重要的主调节因子，参与多种生理功能，包括代谢、增殖、存活、生长、血管生成、迁移和侵袭。Akt蛋白激酶家族包括由不同基因编码的三种高度相关的同种型。Akt亚型共享上游激活子以及若干下游效应子的初步观察，连同高序列同源性一起表明它们的功能大多是冗余的。相比之下，越来越多的证据最近揭示了Akt亚型信号传导特异性的概念，这一概念得到了三种基因中每一种基因经遗传修饰的动物品系所显示的不同表型以及亚型特异性底物的鉴定和与离散亚细胞位置的关联的支持。鉴于Akt被认为是许多病理学中有前途的治疗靶点，因此必须剖析每种亚型的相对贡献以及病理生理功能的补偿程度。在这里，我们总结了我们的观点Akt的选择性是如何实现的背景下，亚细胞定位，异构体特异性底物磷酸化和上下文依赖性功能在正常和病理生理设置。
Akt/PKB is a key master regulator of a wide range of physiological functions including metabolism, proliferation, survival, growth, angiogenesis and migration and invasion. The Akt protein kinase family comprises three highly related isoforms encoded by different genes. The initial observation that the Akt isoforms share upstream activators as well as several downstream effectors, together with the high sequence homology suggested that their functions were mostly redundant. By contrast, an increasing body of evidence has recently uncovered the concept of Akt isoform signaling specificity, supported by distinct phenotypes displayed by animal strains genetically modified for each of the three genes, as well as by the identification of isoform-specific substrates and association with discrete subcellular locations. Given that Akt is regarded as a promising therapeutic target in a number of pathologies, it is essential to dissect the relative contributions of each isoform, as well as the degree of compensation in pathophysiological function. Here we summarize our view of how Akt selectivity is achieved in the context of subcellular localization, isoform-specific substrate phosphorylation and context-dependent functions in normal and pathophysiological settings.