Sun Mei, Yang Lin, Feldman Richard I, Sun Xia-meng, Bhalla Kapil N, Jove Richard, Nicosia Santo V, Cheng Jin Q
Departments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.
J Biol Chem. 2003 Oct 31;278(44):42992-3000. doi: 10.1074/jbc.M306295200. Epub 2003 Aug 21.
Recent studies have demonstrated that the cell growth and antiapoptotic actions of androgen could be dissociated from the transcriptional activity of the receptor and were, instead, mediated by activation of a mitogen-activated protein kinase pathway. This finding suggests an important cellular function of androgen receptor (AR) outside the nucleus. In this report, we demonstrate that androgen activates phosphatidylinositol 3-kinase (PI3K) and Akt, including AKT1 and AKT2, in AR-positive cells. Androgen-induced cell growth and survival were inhibited by PI3K inhibitor and dominant-negative Akt. AR interacts with the p85alpha regulatory subunit of PI3K, and its binding affinity is increased after androgen stimulation. The sites of interaction on the two proteins were mapped to the C-terminal Src-homology 2 domain of p85alpha and N terminus of AR. Activation of PI3K/Akt by androgen was inhibited by dominant-negative Src. Neither N-terminal truncated nor proline-rich region-deleted AR mutants, which are unable to bind to p85alpha and Src, respectively, was able to mediate androgen-induced PI3K/Akt activation. AR with deletion of C-terminal region including ligand binding domain, however, retains the ability to activate PI3K/Akt upon androgen stimulation, which supports the notion that nongenomic function of androgen is mediated by its interaction with membrane receptors (1, 3, 4). These findings indicate that a triple complex between AR, p85alpha, and Src is required for androgen-stimulated PI3K/Akt activation, and that the PI3K/Akt pathway, in addition to mitogen-activated protein kinase, mediates androgen-induced cell growth and cell survival.
最近的研究表明，雄激素的细胞生长和抗凋亡作用可能与其受体的转录活性无关，而是由丝裂原活化蛋白激酶途径的激活介导的。这一发现提示了雄激素受体（AR）在细胞核外的重要细胞功能。在本报告中，我们证明雄激素在AR阳性细胞中激活磷脂酰肌醇3激酶（PI3K）和Akt，包括AKT1和AKT2。PI3K抑制剂和显性负性Akt可抑制雄激素诱导的细胞生长和存活。AR与PI3K的p85α调节亚基相互作用，雄激素刺激后其结合亲和力增加。两种蛋白质上的相互作用位点被定位到p85α的C末端Src同源2结构域和AR的N末端。显性负性Src可抑制雄激素对PI3K/Akt的激活。分别不能与p85α和Src结合的N末端截短型和富含脯氨酸区域缺失型AR突变体均不能介导雄激素诱导的PI3K/Akt激活。然而，缺失包括配体结合结构域在内的C末端区域的AR在雄激素刺激后仍保留激活PI3K/Akt的能力，这支持了雄激素的非基因组功能是由其与膜受体相互作用介导的观点（1,3,4）。这些发现表明，AR、p85α和Src之间的三元复合物是雄激素刺激PI3K/Akt激活所必需的，并且PI3K/Akt途径除了丝裂原活化蛋白激酶外，还介导雄激素诱导的细胞生长和细胞存活。
