Koryakina Yulia, Ta Huy Q, Gioeli Daniel
Department of MicrobiologyImmunology, and Cancer BiologyUVA Cancer CenterUniversity of Virginia, PO Box 800734, Charlottesville, Virginia 22908, USA.
Department of MicrobiologyImmunology, and Cancer BiologyUVA Cancer CenterUniversity of Virginia, PO Box 800734, Charlottesville, Virginia 22908, USADepartment of MicrobiologyImmunology, and Cancer BiologyUVA Cancer CenterUniversity of Virginia, PO Box 800734, Charlottesville, Virginia 22908, USA
Endocr Relat Cancer. 2014 Aug;21(4):T131-45. doi: 10.1530/ERC-13-0472. Epub 2014 Jan 14.
The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is also regulated by post-translational modifications generated by signal transduction pathways. Thus, the AR functions not only as a transcription factor but also as a node that integrates multiple extracellular signals. The AR plays an important role in many diseases, including complete androgen insensitivity syndrome, spinal bulbar muscular atrophy, prostate and breast cancer, etc. In the case of prostate cancer, dependence on AR signaling has been exploited for therapeutic intervention for decades. However, the effectiveness of these therapies is limited in advanced disease due to restoration of AR signaling. Greater understanding of the molecular mechanisms involved in AR action will enable the development of improved therapeutics to treat the wide range of AR-dependent diseases. The AR is subject to regulation by a number of kinases through post-translational modifications on serine, threonine, and tyrosine residues. In this paper, we review the AR phosphorylation sites, the kinases responsible for these phosphorylations, as well as the biological context and the functional consequences of these phosphorylations. Finally, what is known about the state of AR phosphorylation in clinical samples is discussed.
雄激素受体(AR)是一种配体调节的转录因子,属于核受体家族。除了受类固醇调节外,AR还受信号转导途径产生的翻译后修饰的调控。因此,AR不仅作为转录因子发挥作用,还作为整合多种细胞外信号的节点。AR在许多疾病中发挥重要作用,包括完全性雄激素不敏感综合征、脊髓延髓性肌萎缩症、前列腺癌和乳腺癌等。在前列腺癌的情况下,数十年来一直利用对AR信号传导的依赖进行治疗干预。然而,由于AR信号传导的恢复,这些疗法在晚期疾病中的有效性有限。对AR作用所涉及的分子机制有更深入的了解将有助于开发更好的疗法来治疗广泛的AR依赖性疾病。AR受到多种激酶的调控,这些激酶通过对丝氨酸、苏氨酸和酪氨酸残基进行翻译后修饰来实现。在本文中,我们综述了AR的磷酸化位点、负责这些磷酸化的激酶,以及这些磷酸化的生物学背景和功能后果。最后,讨论了临床样本中AR磷酸化状态的已知情况。