PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate

Abstract

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.

Keywords: IRS1; PI3K; PLEKHS1; PTEN; Src-family kinase; prostate.