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

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 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 signalling and constrained by pathway-feedback. In the absence of PTEN, the network is dramatically remodelled. 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-signalling and supports tumour progression.