Two Sides of the Same Coin: Protein Kinase C γ in Cancer and Neurodegeneration.
Two Sides of the Same Coin: Protein Kinase C γ in Cancer and Neurodegeneration.
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DOI：
10.3389/fcell.2022.929510
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发表时间：
2022
影响因子：
5.5
通讯作者：
Newton AC
中科院分区：
文献类型：
--
作者：
Pilo CA;Newton AC
蛋白激酶 C (PKC) 同工酶可在细胞内转导无数信号，以响应膜磷脂第二信使的生成。传统的同工酶 PKCγ 可逆地结合 Ca2+ 和二酰甘油，从而形成开放的活性构象。 PKCγ 表达通常仅限于神经元，但其在某些癌症中表达的证据已经出现。自从发现 PKC 同工酶与促进肿瘤的佛波酯结合以来，它们就被标记为致癌基因，然而，对癌症相关 PKC 突变的研究和显示 PKC 抑制剂使患者生存恶化的临床试验数据已将 PKC 重新定义为肿瘤抑制因子。 PKCγ 在某些癌症中的异常表达表明 PKCγ 在大脑之外发挥作用，尽管 PKCγ 是否也充当肿瘤抑制因子仍有待确定。另一方面，与脊髓小脑共济失调 14 型 (SCA14) 相关的 PKCγ 变体（一种以浦肯野细胞变性为特征的神经退行性疾病）增强基础活性，同时防止佛波酯介导的降解。尽管 SCA14 浦肯野细胞变性的基础仍然未知，但研究已经揭示了改变的 PKCγ 活性如何重新连接小脑信号以驱动 SCA14。重要的是，SCA14 相关突变体基础活性的增强与发病年龄呈负相关，这支持增强的 PKCγ 活性驱动 SCA14。因此，SCA14 中的 PKCγ 活性很可能受到抑制，而恢复 PKC 活性应该是癌症治疗的目标。这篇综述描述了 PKCγ 活性如何在疾病中丢失或增加，以及对 PKC 结构作为预测 PKCγ 突变对疾病影响的强大工具的首要需求。
Protein kinase C (PKC) isozymes transduce myriad signals within the cell in response to the generation of second messengers from membrane phospholipids. The conventional isozyme PKCγ reversibly binds Ca2+ and diacylglycerol, which leads to an open, active conformation. PKCγ expression is typically restricted to neurons, but evidence for its expression in certain cancers has emerged. PKC isozymes have been labeled as oncogenes since the discovery that they bind tumor-promoting phorbol esters, however, studies of cancer-associated PKC mutations and clinical trial data showing that PKC inhibitors have worsened patient survival have reframed PKC as a tumor suppressor. Aberrant expression of PKCγ in certain cancers suggests a role outside the brain, although whether PKCγ also acts as a tumor suppressor remains to be established. On the other hand, PKCγ variants associated with spinocerebellar ataxia type 14 (SCA14), a neurodegenerative disorder characterized by Purkinje cell degeneration, enhance basal activity while preventing phorbol ester-mediated degradation. Although the basis for SCA14 Purkinje cell degeneration remains unknown, studies have revealed how altered PKCγ activity rewires cerebellar signaling to drive SCA14. Importantly, enhanced basal activity of SCA14-associated mutants inversely correlates with age of onset, supporting that enhanced PKCγ activity drives SCA14. Thus, PKCγ activity should likely be inhibited in SCA14, whereas restoring PKC activity should be the goal in cancer therapies. This review describes how PKCγ activity can be lost or gained in disease and the overarching need for a PKC structure as a powerful tool to predict the effect of PKCγ mutations in disease.
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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：
--
作者：
Antal, Corina E.;Violin, Jonathan D.;Newton, Alexandra C.
通讯作者：
Newton, Alexandra C.
影响因子：
4.1
作者：
Garcia-Paramio, P;Cabrerizo, Y;Parker, PJ
通讯作者：
Parker, PJ
影响因子：
6.1
作者：
Ji, Jingmin;Hassler, Melanie L.;Kapfhammer, Josef P.
通讯作者：
Kapfhammer, Josef P.
影响因子：
7.3
作者：
Baffi TR;Lordén G;Wozniak JM;Feichtner A;Yeung W;Kornev AP;King CC;Del Rio JC;Limaye AJ;Bogomolovas J;Gould CM;Chen J;Kennedy EJ;Kannan N;Gonzalez DJ;Stefan E;Taylor SS;Newton AC
通讯作者：
Newton AC