Mammalian phosphatidylinositol 4-kinases as modulators of membrane trafficking and lipid signaling networks.
Mammalian phosphatidylinositol 4-kinases as modulators of membrane trafficking and lipid signaling networks.
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DOI：
10.1016/j.plipres.2013.04.002
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发表时间：
2013-07
影响因子：
13.6
通讯作者：
Waugh, Mark G.
中科院分区：
文献类型：
--
作者：
Clayton, Emma L.;Minogue, Shane;Waugh, Mark G.
四种哺乳动物磷脂酰肌醇4-激酶调节细胞器间脂质运输、磷脂肌醇信号传导和细胞内囊泡运输。除了合成PI4P所需的催化结构域外，磷脂酰肌醇4-激酶还含有与AP-3和E3泛素连接酶Itch等蛋白相互作用的异构体特异性结构基元，这种结构差异决定了异构体在膜运输中的作用。此外，磷脂酰肌醇4-激酶同工酶的不同排列可能需要单个细胞功能，例如发生在GPCR信号传导的不同阶段和高尔基体到溶酶体运输中。磷脂酰肌醇4激酶最近与人类疾病有关。新出现的范例包括在某些癌症中磷脂酰肌醇4-激酶表达增加，与神经病理学相关的功能受损，细菌感染中PI4P转运功能的颠覆以及病毒性疾病中脂激酶活性的激活。我们讨论了磷脂酰肌醇4-激酶的多样性和有时重叠的功能如何在治疗背景下为设计异构体特异性抑制剂提出挑战。
The four mammalian phosphatidylinositol 4-kinases modulate inter-organelle lipid trafficking, phosphoinositide signalling and intracellular vesicle trafficking. In addition to catalytic domains required for the synthesis of PI4P, the phosphatidylinositol 4-kinases also contain isoform-specific structural motifs that mediate interactions with proteins such as AP-3 and the E3 ubiquitin ligase Itch, and such structural differences determine isoform-specific roles in membrane trafficking. Moreover, different permutations of phosphatidylinositol 4-kinase isozymes may be required for a single cellular function such as occurs during distinct stages of GPCR signalling and in Golgi to lysosome trafficking. Phosphatidylinositol 4-kinases have recently been implicated in human disease. Emerging paradigms include increased phosphatidylinositol 4-kinase expression in some cancers, impaired functioning associated with neurological pathologies, the subversion of PI4P trafficking functions in bacterial infection and the activation of lipid kinase activity in viral disease. We discuss how the diverse and sometimes overlapping functions of the phosphatidylinositol 4-kinases present challenges for the design of isoform-specific inhibitors in a therapeutic context.
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