Liu X, Hu Y, Hao C, Rempel S A, Ye K
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Oncogene. 2007 Jul 26;26(34):4918-27. doi: 10.1038/sj.onc.1210290. Epub 2007 Feb 12.
PIKE-A (phosphoinositide 3-kinases (PI 3)-kinase enhancer) is a ubiquitously expressed GTPase, which binds to and enhances protein kinase B (Akt) kinase activity in a guanine nucleotide-dependent manner. PIKE-A is one of the components of the CDK4 amplicon that is amplified in numerous human cancers. However, whether PIKE-A itself can mediate cell transformation, proliferation and migration remains unknown. Here, we show that PIKE-A is overexpressed in various human cancer samples, escalates U87MG glioblastoma invasion and provokes NIH3T3 cell transformation. Overexpression of wild-type (WT) PIKE-A enhances NIH3T3 and U87MG cell growth, which is further increased by cancer cell-derived PIKE-A active mutants. In contrast, both the dominant-negative mutant and the phosphoinositide lipids interaction-defective mutant antagonize cell proliferation. Moreover, PIKE-A and its active and inactive mutants similarly enhance or antagonize U87MG cell survival and invasion, and their ability to do so is coupled with the catalytic effect they have on Akt activation. Furthermore, PIKE-A WT and its active mutants significantly elicit NIH3T3 cell transformation. Thus, our findings support the concept that PIKE-A acts as a proto-oncogene, promoting cell transformation through Akt activation.
PIKE - A（磷脂酰肌醇3 -激酶（PI 3）激酶增强子）是一种广泛表达的GTP酶，它以鸟嘌呤核苷酸依赖的方式与蛋白激酶B（Akt）结合并增强其激酶活性。PIKE - A是细胞周期蛋白依赖性激酶4（CDK4）扩增子的组成成分之一，该扩增子在多种人类癌症中发生扩增。然而，PIKE - A自身是否能介导细胞转化、增殖和迁移仍不清楚。在此，我们表明PIKE - A在各种人类癌症样本中过表达，加剧U87MG胶质母细胞瘤的侵袭并引发NIH3T3细胞转化。野生型（WT）PIKE - A的过表达增强了NIH3T3和U87MG细胞的生长，癌细胞来源的PIKE - A活性突变体进一步增强了这种生长。相反，显性负性突变体和磷脂酰肌醇脂质相互作用缺陷突变体均拮抗细胞增殖。此外，PIKE - A及其活性和非活性突变体同样增强或拮抗U87MG细胞的存活和侵袭，并且它们这样做的能力与其对Akt激活的催化作用相关。此外，PIKE - A野生型及其活性突变体显著引发NIH3T3细胞转化。因此，我们的研究结果支持PIKE - A作为原癌基因通过激活Akt促进细胞转化这一概念。
