Hofmann J
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
FASEB J. 1997 Jul;11(8):649-69. doi: 10.1096/fasebj.11.8.9240967.
Protein kinase C (PKC) is a phospholipid-dependent serine/threonine kinase family consisting of at least 11 closely related isoenzymes. The different PKC isoenzymes play important roles in signal transduction pathways. The exact significance of each isoenzyme is not known at present; therefore, the elucidation of the roles of the various PKC isoenzymes is important. To explain the function of distinct PKC isoenzymes, the availability of isoenzyme-specific inhibibitors or activators would be an advantage. PKC inhibitors have been known for some time, but these compounds are not isoenzyme-specific and also inhibit other kinases. Recently, an inhibitor selective for PKC alpha and another one selective for PKCbetaI and betaII were described. Both compounds compete with the ATP binding sites that exhibit high homologies among the different PKC isoenzymes. Among others, the phosporyl transfer region, the pseudosubstrate domain, the phorbolester binding sequences, and the phosphorylation sites may also be targets for modulation of isoenzyme-specific PKC activity. The question is whether the differences in these domains and the substrate specificity of the PKC isoenzymes will allow isoenzyme-specific inhibition. In this review the human sequences of these sites, isoenzyme-specific substrates, inhibitory compounds, and inhibitory peptides are summarized.
蛋白激酶C（PKC）是一个依赖磷脂的丝氨酸/苏氨酸激酶家族，由至少11种密切相关的同工酶组成。不同的PKC同工酶在信号转导途径中发挥重要作用。目前每种同工酶的确切意义尚不清楚；因此，阐明各种PKC同工酶的作用很重要。为了解释不同PKC同工酶的功能，获得同工酶特异性抑制剂或激活剂将是一个优势。PKC抑制剂已被人们所知一段时间了，但这些化合物并非同工酶特异性的，还会抑制其他激酶。最近，描述了一种对PKCα有选择性的抑制剂和另一种对PKCβI和βII有选择性的抑制剂。这两种化合物都与不同PKC同工酶中具有高度同源性的ATP结合位点竞争。此外，磷酰转移区域、假底物结构域、佛波酯结合序列和磷酸化位点也可能是调节同工酶特异性PKC活性的靶点。问题在于这些结构域的差异以及PKC同工酶的底物特异性是否能实现同工酶特异性抑制。在这篇综述中，总结了这些位点的人类序列、同工酶特异性底物、抑制性化合物和抑制性肽。
