Wick K L, Liu F
Departments of Pharmacology, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
Curr Drug Targets Immune Endocr Metabol Disord. 2001 Nov;1(3):209-21. doi: 10.2174/1568008013341082.
Over the last several years, a great level of interest has rallied behind understanding how the pivotal kinase, 3'-phosphoinositide dependent kinase 1 (PDK1) is regulated. PDK1 phosphorylates and activates members of the AGC kinase family shown to be activated downstream of phosphoinositide 3-kinase (P13K); however, the functional dependency of PDK1 on P13K for activation of its targets is less clear. The P13K signaling pathway mediates numerous cellular responses upon growth factor and hormone stimulation. Specifically, P13K signaling influences many of the metabolic and mitogenic functions of the anabolic hormone, insulin. Thus, the regulation of P13K and its downstream targets by insulin has become an important topic for investigation. Given its central role as the kinase upstream of those signaling pathways linked to P13K, the regulation of PDK1 by insulin and other factors is at the height of many of these investigations. Current theories on PDK1 regulation propose substrate conformation and subcellular localization as the primary mediators of PDK1 function. The array of PDK1 substrates suggests, however, that in cells PDK1 may be more tightly regulated. Recent data support phosphorylation as a potential regulatory mechanism that may play an additional role in directing the specificity of PDK1 towards its physiological substrates. The combination of these regulatory mechanisms along with the potential for multiple PDK1 isoforms with select tissue distribution may contribute to the diversified actions of insulin signaling. The targeting of these various aspects of PDK1 regulation may provide for novel therapeutic treatments for diseases such as diabetes and cancer.
在过去几年中，人们对了解关键激酶3'-磷酸肌醇依赖性激酶1（PDK1）的调控方式产生了浓厚兴趣。PDK1可磷酸化并激活AGC激酶家族成员，这些成员在磷酸肌醇3激酶（PI3K）下游被激活；然而，PDK1在激活其靶标方面对PI3K的功能依赖性尚不清楚。PI3K信号通路在生长因子和激素刺激后介导多种细胞反应。具体而言，PI3K信号影响合成代谢激素胰岛素的许多代谢和促有丝分裂功能。因此，胰岛素对PI3K及其下游靶标的调控已成为一个重要的研究课题。鉴于PDK1作为与PI3K相关信号通路上游激酶的核心作用，胰岛素和其他因素对PDK1的调控是许多此类研究的重点。目前关于PDK1调控的理论认为底物构象和亚细胞定位是PDK1功能的主要调节因子。然而，一系列PDK1底物表明，在细胞中PDK1可能受到更严格的调控。最近的数据支持磷酸化作为一种潜在的调控机制，可能在指导PDK1对其生理底物的特异性方面发挥额外作用。这些调控机制与具有特定组织分布的多种PDK1亚型的可能性相结合，可能有助于胰岛素信号的多样化作用。针对PDK1调控的这些不同方面可能为糖尿病和癌症等疾病提供新的治疗方法。
