Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany.
Am J Physiol Endocrinol Metab. 2012 Jun 15;302(12):E1453-60. doi: 10.1152/ajpendo.00660.2011. Epub 2012 Feb 21.
The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt- and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt- and mTOR-signaling network in health and disease.
富含脯氨酸的 Akt 底物 40kDa（PRAS40）在 Akt 和雷帕霉素靶蛋白（mTOR）介导的信号通路的交汇点发挥作用。蛋白激酶 mTOR 是两种不同信号复合物的催化亚基，mTOR 复合物 1（mTORC1）和 mTORC2，它们将能量和营养物质与细胞生长和能量代谢的调节联系起来。mTOR 对营养物质和生长因子的激活导致许多底物的磷酸化，包括 mTORC1 对 S6 激酶的磷酸化和 mTORC2 对 Akt 的磷酸化。Akt 和 mTOR 活性的改变与多种疾病的进展有关，如癌症和 2 型糖尿病。尽管 PRAS40 最初被报道为 Akt 的底物，但随后对 mTOR 结合伙伴的研究将 PRAS40 鉴定为 mTORC1 的组成部分和底物。Akt 和 mTORC1 自身对 PRAS40 的磷酸化导致 PRAS40 从 mTORC1 解离，并可能解除对 mTORC1 活性的抑制约束。更复杂的是，基因沉默研究表明 PRAS40 对于 mTORC1 复合物的活性也是必需的。这篇综述总结了 PRAS40 在健康和疾病中复杂的 Akt 和 mTOR 信号网络中的调节和潜在功能。
