Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia.
Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
Int J Mol Sci. 2021 Jun 28;22(13):6944. doi: 10.3390/ijms22136944.
The PI3K/mTOR signalling pathway plays a central role in the governing of cell growth, survival and metabolism. As such, it must integrate and decode information from both external and internal sources to guide efficient decision-making by the cell. To facilitate this, the pathway has evolved an intricate web of complex regulatory mechanisms and elaborate crosstalk with neighbouring signalling pathways, making it a highly non-linear system. Here, we describe the mechanistic biological details that underpin these regulatory mechanisms, covering a multitude of negative and positive feedback loops, feed-forward loops, competing protein interactions, and crosstalk with major signalling pathways. Further, we highlight the non-linear and dynamic network behaviours that arise from these regulations, uncovered through computational and experimental studies. Given the pivotal role of the PI3K/mTOR network in cellular homeostasis and its frequent dysregulation in pathologies including cancer and diabetes, a coherent and systems-level understanding of the complex regulation and consequential dynamic signalling behaviours within this network is imperative for advancing biology and development of new therapeutic approaches.
PI3K/mTOR 信号通路在调节细胞生长、存活和代谢方面起着核心作用。因此，它必须整合和解码来自外部和内部的信息，指导细胞做出有效的决策。为此，该通路进化出了复杂的调控机制网络，并与相邻信号通路进行了精细的相互作用，使其成为一个高度非线性的系统。在这里，我们描述了这些调控机制的机械生物学细节，涵盖了多种负反馈回路、正反馈回路、竞争蛋白相互作用以及与主要信号通路的相互作用。此外，我们还强调了通过计算和实验研究揭示的来自这些调控的非线性和动态网络行为。鉴于 PI3K/mTOR 网络在细胞内稳态中的关键作用，以及其在包括癌症和糖尿病在内的病理学中经常失调，因此，对该网络中复杂调控及其随之而来的动态信号转导行为进行一致的、系统水平的理解，对于推进生物学和开发新的治疗方法至关重要。
