Denley A, Kang S, Karst U, Vogt P K
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Oncogene. 2008 Apr 17;27(18):2561-74. doi: 10.1038/sj.onc.1210918. Epub 2007 Nov 12.
The catalytic subunits of class I PI3Ks comprise four isoforms: p110alpha, p110beta, p110delta and p110gamma. Cancer-specific gain-of-function mutations in p110alpha have been identified in various malignancies. Cancer-specific mutations in the non-alpha isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110beta, p110gamma or p110delta is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-alpha isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3beta and cause degradation of FoxO1. A functional Erk pathway is required for p110gamma and p110beta transformation but not for transformation by p110delta or the H1047R mutant of p110alpha. Transformation and signaling by p110gamma and p110beta are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110delta reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110beta and p110gamma.
I类PI3K的催化亚基包含四种异构体：p110α、p110β、p110δ和p110γ。在各种恶性肿瘤中已鉴定出p110α的癌症特异性功能获得性突变。然而，尚未鉴定出I类PI3K非α异构体的癌症特异性突变，不过野生型p110β、p110γ或p110δ的过表达足以在鸡胚成纤维细胞中诱导细胞转化。I类这些非α异构体介导致癌信号的机制尚不清楚。在此我们表明，具有高效转化能力的I类异构体通过Akt/mTOR发出信号，抑制GSK3β并导致FoxO1降解。p110γ和p110β转化需要功能性的Erk途径，但p110δ或p110α的H1047R突变体转化则不需要。p110γ和p110β的转化和信号传导对与作为膜锚定物的Ras相互作用的丧失敏感。p110δ的C2结构域突变会降低转化，最可能是通过干扰膜结合。几种小分子抑制剂能有效且特异性地抑制每种I类PI3K的致癌信号传导和转化，并且当与MEK抑制剂联合使用时，可累加地降低p110β和p110γ诱导的转化。
