Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK.
Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK.
Mol Cell. 2023 Aug 17;83(16):2991-3009.e13. doi: 10.1016/j.molcel.2023.07.015. Epub 2023 Aug 10.
The PIP/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP/PI(3,4)P phosphatase, PTEN. Despite huge research investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signaling and constrained by pathway feedback. In the absence of PTEN, the network is dramatically remodeled. A poorly understood YXXM- and PIP/PI(3,4)P-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP, AKT phosphorylation, and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and Src-family kinase-dependent phosphorylation of YXXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y phosphorylation of hSrc correlated with PI3K pathway activity in human prostate cancers. We propose that in PTEN-null cells receptor-independent, Src-dependent tyrosine phosphorylation of PLEKHS1 creates positive feedback that escapes homeostasis, drives PIP signaling, and supports tumor progression.
PIP/PI3K 网络是代谢的核心调节剂，在癌症中经常被激活，通常是由于 PIP/PI(3,4)P 磷酸酶 PTEN 的缺失。尽管投入了大量的研究资金，但正常组织中 PI3K 网络的驱动因素以及它们如何适应过度激活仍不清楚。我们发现，在健康的小鼠前列腺中，PI3K 活性由 RTK/IRS 信号驱动，并受到途径反馈的限制。在没有 PTEN 的情况下，该网络发生了显著的重构。一种尚未被充分了解的 YXXM-和 PIP/PI(3,4)P 结合 PH 结构域包含的衔接蛋白 PLEKHS1 成为主要的激活剂，并需要维持 PIP、AKT 磷酸化和 PTEN 缺失的前列腺中的生长。这是因为 PLEKHS1 逃避了途径反馈，并经历了增强的 PI3K 和 Src 家族激酶依赖性 YXXM 磷酸化，引发了 PI3K 激活。hPLEKHS1 mRNA 和 hSrc 的激活 Y 磷酸化与人类前列腺癌中的 PI3K 途径活性相关。我们提出，在 PTEN 缺失的细胞中，Src 依赖性 PLEKHS1 的非受体依赖性酪氨酸磷酸化会产生正反馈，从而逃避体内平衡，驱动 PIP 信号，并支持肿瘤进展。
