Zhao L, Vogt P K
Division of Oncovirology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Oncogene. 2008 Sep 18;27(41):5486-96. doi: 10.1038/onc.2008.244.
Class I phosphoinositide 3-kinase (PI3K) is a dimeric enzyme, consisting of a catalytic and a regulatory subunit. The catalytic subunit occurs in four isoforms designated as p110 alpha, p110 beta, p110 gamma and p110 delta. These isoforms combine with several regulatory subunits; for p110 alpha, beta and delta, the standard regulatory subunit is p85, for p110 gamma, it is p101. PI3Ks play important roles in human cancer. PIK3CA, the gene encoding p110 alpha, is mutated frequently in common cancers, including carcinoma of the breast, prostate, colon and endometrium. Eighty percent of these mutations are represented by one of the three amino-acid substitutions in the helical or kinase domains of the enzyme. The mutant p110 alpha shows a gain of function in enzymatic and signaling activity and is oncogenic in cell culture and in animal model systems. Structural and genetic data suggest that the mutations affect regulatory inter- and intramolecular interactions and support the conclusion that there are at least two molecular mechanisms for the gain of function in p110 alpha. One of these mechanisms operates largely independently of binding to p85, the other abolishes the requirement for an interaction with Ras. The non-alpha isoforms of p110 do not show cancer-specific mutations. However, they are often differentially expressed in cancer and, in contrast to p110 alpha, wild-type non-alpha isoforms of p110 are oncogenic when overexpressed in cell culture. The isoforms of p110 have become promising drug targets. Isoform-selective inhibitors have been identified. Inhibitors that target exclusively the cancer-specific mutants of p110 alpha constitute an important goal and challenge for current drug development.
I类磷酸肌醇3激酶（PI3K）是一种二聚体酶，由一个催化亚基和一个调节亚基组成。催化亚基有四种异构体，分别命名为p110α、p110β、p110γ和p110δ。这些异构体与几种调节亚基结合；对于p110α、β和δ，标准调节亚基是p85，对于p110γ，是p101。PI3K在人类癌症中发挥重要作用。编码p110α的基因PIK3CA在常见癌症中经常发生突变，包括乳腺癌、前列腺癌、结肠癌和子宫内膜癌。这些突变中有80%由该酶螺旋或激酶结构域中的三种氨基酸替代之一表示。突变型p110α在酶活性和信号传导活性方面表现出功能获得，并且在细胞培养和动物模型系统中具有致癌性。结构和遗传数据表明，这些突变影响调节性分子间和分子内相互作用，并支持以下结论：p110α功能获得至少有两种分子机制。其中一种机制在很大程度上独立于与p85的结合起作用，另一种机制消除了与Ras相互作用的需求。p110的非α异构体未显示癌症特异性突变。然而，它们在癌症中常常差异表达，并且与p110α相反，p110的野生型非α异构体在细胞培养中过表达时具有致癌性。p110的异构体已成为有前景的药物靶点。已经鉴定出异构体选择性抑制剂。专门针对p110α癌症特异性突变体的抑制剂是当前药物开发的一个重要目标和挑战。
