PIP3/PI3K网络是代谢的中央调控者，在癌症中常常因PIP3/PI(3,4)P2磷酸酯酶PTEN的丧失而被激活。尽管进行了大量的研究投资，正常组织中PI3K网络的驱动因素以及其如何适应过度活化仍然不清楚。我们发现在健康的小鼠前列腺中，PI3K活性由RTK/IRS信号驱动，并受到通路反馈的限制。在PTEN缺失的情况下，网络会发生明显的重组。一个尚不完全理解的YXXM和PIP3/PI(3,4)P2结合的PH区域含有适配体PLEKHS1成为主要的激活因子，并且必须维持PIP3、AKT磷酸化和PTEN零抑制的前列腺生长。这是因为PLEKHS1逃避了通路反馈，并且经历了增强的PI3K和Src家族激酶依赖的Y258XXM磷酸化，从而引发PI3K活化。hPLEKHS1 mRNA和hSrc的激活Y419磷酸化与人前列腺癌中PI3K通路的活性相关。我们提出，在PTEN缺失的细胞中，无受体依赖、Src依赖的酪氨酸磷酸化PL（同质性域结构1）促使逃逸稳态平衡的正向反馈，驱动PIP3信号传导，并支持肿瘤进展。本文所有权归2023年作者所有。由Elsevier Inc.发表，保留所有权利。

The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2 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 PIP3/PI(3,4)P2-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, 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 Y258XXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y419 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 PIP3 signaling, and supports tumor progression.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.