Lee Suzanne R, Ramos Sharon M, Ko Andrew, Masiello David, Swanson Kenneth D, Lu Michael L, Balk Steven P
Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Mol Endocrinol. 2002 Jan;16(1):85-99. doi: 10.1210/mend.16.1.0753.
A human protein termed p21-activated kinase 6 (PAK6), based on homology to the PAK family of serine/threonine kinases, was cloned as an AR interacting protein. PAK6 was a 75-kDa protein with a predicted N-terminal Cdc42/Rac interactive binding domain and a C-terminal kinase domain. PAK6 bound strongly to GTP-Cdc42 and weakly to GTP-Rac. In contrast to most PAKs, kinase activity was not stimulated by Cdc42 or Rac, but could be stimulated by AR binding. PAK6 interacted with the intact AR in a mammalian one-hybrid assay and bound in vitro, without ligand, to the hinge region between the AR DNA- and ligand-binding domains. PAK6 also bound to the ERalpha, and binding was enhanced by 4-hydroxytamoxifen. AR and ERalpha transcriptional activities were inhibited by PAK6 in transient transfections with episomal and integrated reporter genes. AR inhibition was not reversed by transfection with an activated Cdc42 mutant, Cdc42V12, which by itself also inhibited AR transactivation. Epitope-tagged PAK6 was primarily cytoplasmic in the absence or presence of AR and hormone. PAK6 transcripts were expressed most highly in brain and testis, with lower levels in multiple tissues including prostate and breast. PAK6 interaction provides a mechanism for cross-talk between steroid hormone receptors and Cdc42-mediated signal transduction pathways and could contribute to the effects of tamoxifen in breast cancer and in other tissues.
一种基于与丝氨酸/苏氨酸激酶PAK家族的同源性而被命名为p21活化激酶6（PAK6）的人类蛋白质，作为一种与雄激素受体（AR）相互作用的蛋白质被克隆出来。PAK6是一种75kDa的蛋白质，具有一个预测的N端Cdc42/Rac相互作用结合结构域和一个C端激酶结构域。PAK6与GTP-Cdc42强烈结合，与GTP-Rac弱结合。与大多数PAK不同，其激酶活性不受Cdc42或Rac的刺激，但可被AR结合所刺激。在哺乳动物单杂交试验中，PAK6与完整的AR相互作用，并且在无配体的情况下在体外与AR的DNA结合结构域和配体结合结构域之间的铰链区结合。PAK6也与雌激素受体α（ERα）结合，并且4-羟基他莫昔芬可增强这种结合。在用游离型和整合型报告基因进行的瞬时转染中，PAK6抑制AR和ERα的转录活性。用活化的Cdc42突变体Cdc42V12转染不能逆转AR的抑制作用，而Cdc42V12本身也抑制AR的反式激活。无论有无AR和激素，表位标记的PAK6主要位于细胞质中。PAK6转录本在脑和睾丸中表达最高，在包括前列腺和乳腺在内的多个组织中表达水平较低。PAK6的相互作用为类固醇激素受体与Cdc42介导的信号转导途径之间的串扰提供了一种机制，并且可能有助于他莫昔芬在乳腺癌和其他组织中的作用。
