A partnership with the proteasome; the destructive nature of GSK3.
A partnership with the proteasome; the destructive nature of GSK3.
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DOI：
10.1016/j.bcp.2017.10.016
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发表时间：
2018-01
影响因子：
5.8
通讯作者：
Sutherland C
中科院分区：
文献类型：
--
作者：
Robertson H;Hayes JD;Sutherland C
糖原合成酶激酶3（Glycogen Synthase Kinase-3，GSK 3）最初被报道为通过调节糖原合成速率来维持葡萄糖稳态的关键酶。随后发现它影响大多数细胞过程，包括生长、分化和死亡，作为其调节对激素、营养和细胞应激刺激的反应的作用的一部分。已经提出了超过100种针对GSK 3的蛋白质靶点，尽管其中只有一小部分在生理细胞系统中得到了令人信服的验证。GSK 3磷酸化对底物的影响包括酶活性、蛋白质定位、蛋白质：蛋白质相互作用和蛋白质稳定性的改变。这后一种形式的GSK 3底物的监管是本次审查的重点。有越来越多的GSK 3底物在磷酸化后靶向含β-转导蛋白重复序列的蛋白（β-TrCP），从而允许cullin-1对结合蛋白进行泛素化，从而引发蛋白酶体的破坏。我们提出存在GSK 3-β-TrCP“破坏命中列表”，其允许通过控制GSK 3协调去除（或稳定）具有共同生理目的的一组蛋白质。我们鉴定了29种蛋白质，其中有相对强有力的证据表明它们受GSK 3-β-TrCP轴调控，并注意到调控和病理生理学的共同特征。此外，我们评估了这些靶点的预磷酸化（引发）的潜力（通常是GSK 3识别的先决条件），以提供由引发激酶描绘的第二层调节，允许GSK 3标记它们以进行破坏。最后，我们讨论了这些知识是否改善了治疗干预的选择。
Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems. The effects of GSK3 phosphorylation on substrates include alteration of enzyme activity, protein localisation, protein:protein interaction and protein stability. This latter form of regulation of GSK3 substrates is the focus of this review. There is an ever-growing list of GSK3 substrates that upon phosphorylation are targeted to the beta-transducin repeat containing protein (β-TrCP), thereby allowing ubiquitination of bound protein by cullin-1 and so initiating destruction at the proteasome. We propose the existence of a GSK3-β-TrCP ‘destruction hit-list’ that allows co-ordinated removal (or stabilisation) of a set of proteins with a common physiological purpose, through control of GSK3. We identify 29 proteins where there is relatively strong evidence for regulation by a GSK3-β-TrCP axis and note common features of regulation and pathophysiology. Furthermore, we assess the potential of pre-phosphorylation (priming) of these targets (normally a prerequisite for GSK3 recognition) to provide a second layer of regulation delineated by the priming kinase that allows GSK3 to mark them for destruction. Finally, we discuss whether this knowledge improves options for therapeutic intervention.
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