Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
Semin Cell Dev Biol. 2011 Sep;22(7):713-9. doi: 10.1016/j.semcdb.2011.08.008. Epub 2011 Aug 22.
Thirty years ago, it was discovered that 14-3-3 proteins could activate enzymes involved in amino acid metabolism. In the following decades, 14-3-3s have been shown to be involved in many different signaling pathways that modulate cellular and whole body energy and nutrient homeostasis. Large scale screening for cellular binding partners of 14-3-3 has identified numerous proteins that participate in regulation of metabolic pathways, although only a minority of these targets have yet been subject to detailed studies. Because of the wide distribution of potential 14-3-3 targets and the resurging interest in metabolic pathway control in diseases like cancer, diabetes, obesity and cardiovascular disease, we review the role of 14-3-3 proteins in the regulation of core and specialized cellular metabolic functions. We cite illustrative examples of 14-3-3 action through their direct modulation of individual enzymes and through regulation of master switches in cellular pathways, such as insulin signaling, mTOR- and AMP dependent kinase signaling pathways, as well as regulation of autophagy. We further illustrate the quantitative impact of 14-3-3 association on signal response at the target protein level and we discuss implications of recent findings showing 14-3-3 protein membrane binding of target proteins.
三十年前，人们发现 14-3-3 蛋白可以激活参与氨基酸代谢的酶。在接下来的几十年里，已经证实 14-3-3 参与了许多不同的信号通路，这些信号通路调节细胞和全身的能量和营养稳态。对 14-3-3 的细胞结合伙伴进行大规模筛选，鉴定出许多参与代谢途径调节的蛋白质，尽管这些靶点中只有少数已进行详细研究。由于潜在的 14-3-3 靶点分布广泛，以及对癌症、糖尿病、肥胖症和心血管疾病等疾病中代谢途径控制的兴趣再次兴起，我们综述了 14-3-3 蛋白在调节核心和专门的细胞代谢功能中的作用。我们通过直接调节个别酶以及通过调节细胞途径中的主开关（如胰岛素信号、mTOR 和 AMP 依赖性激酶信号通路），以及自噬的调节，举例说明了 14-3-3 的作用。我们进一步说明了 14-3-3 与目标蛋白结合对目标蛋白水平信号响应的定量影响，并讨论了最近发现的显示 14-3-3 蛋白与目标蛋白的膜结合的意义。
