Protein kinase C: perfectly balanced.
Protein kinase C: perfectly balanced.
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DOI：
10.1080/10409238.2018.1442408
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发表时间：
2018-04
影响因子：
6.5
通讯作者：
Newton AC
中科院分区：
文献类型：
--
作者：
Newton AC
蛋白激酶C（PKC）同工酶属于丝氨酸/苏氨酸激酶家族，其活性由自身抑制性假底物的可逆释放控制。对于常规和新型同工酶，这是通过结合脂质第二信使，甘油二酯，但对于非典型的PKC同工酶，这是通过结合蛋白质支架的影响。在20世纪80年代发现二酰基甘油敏感的同工酶是有效的促肿瘤佛波酯的“受体”后，PKC成为人们关注的焦点。这就确立了PKC同工酶是癌蛋白的概念。然而，三十年来针对PKC抑制剂的癌症临床试验失败了，在某些情况下，恶化了患者的预后。来自癌症相关突变和蛋白质表达水平的新证据提供了一个原因：蛋白激酶C同工酶通常起肿瘤抑制剂的作用，在癌症治疗中应恢复而不是抑制其活性。虽然没有足够的活性与癌症有关，但活性增强的变体与退行性疾病如阿尔茨海默病有关。本文综述了确保PKC活性完全平衡的严格控制机制，以及当这些控制解除时会发生什么。蛋白激酶C同工酶是孔子智慧的典范：“超越与不足一样错误。”
Protein kinase C (PKC) isozymes belong to a family of Ser/Thr kinases whose activity is governed by reversible release of an autoinhibitory pseudosubstrate. For conventional and novel isozymes, this is effected by binding the lipid second messenger, diacylglycerol, but for atypical PKC isozymes, this is effected by binding protein scaffolds. PKC shot into the limelight following the discovery in the 1980s that the diacylglycerol-sensitive isozymes are ‘receptors’ for the potent tumor-promoting phorbol esters. This set in place a concept that PKC isozymes are oncoproteins. Yet three decades of cancer clinical trials targeting PKC with inhibitors failed and, in some cases, worsened patient outcome. Emerging evidence from cancer-associated mutations and protein expression levels provide a reason: protein kinase C isozymes generally function as tumor suppressors and their activity should be restored, not inhibited, in cancer therapies. And whereas not enough activity is associated with cancer, variants with enhanced activity are associated with degenerative diseases such as Alzheimer’s disease. This review describes the tightly controlled mechanisms that ensure PKC activity is perfectly balanced and what happens when these controls are deregulated. PKC isozymes serve as a paradigm for the wisdom of Confucius: “to go beyond is as wrong as to fall short.”
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影响因子：
64.5
作者：
Antal CE;Hudson AM;Kang E;Zanca C;Wirth C;Stephenson NL;Trotter EW;Gallegos LL;Miller CJ;Furnari FB;Hunter T;Brognard J;Newton AC
通讯作者：
Newton AC
影响因子：
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作者：
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通讯作者：
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影响因子：
2.6
作者：
Bowers, BJ;Collins, AC;Wehner, JM
通讯作者：
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影响因子：
64.8
作者：
Betschinger, J;Mechtler, K;Knoblich, JA
通讯作者：
Knoblich, JA
影响因子：
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作者：
Bernatsky, S;Boivin, JF;Clarke, A
通讯作者：
Clarke, A