PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and 1RS-1/Grb-2/Sos complex formation in a breast cancer model

The tumour suppressor gene PTEN encodes a dual-specifity phosphatase that r ecognizes protein substrates and phosphatidylinositol-3,4,5-triphosphate. P TEN seems to play multiple roles in tumour suppression and the blockade of phosphoinositide-3-kinase signalling is important for its growth suppressiv e effects, although precise mechanisms are not fully understood. In this st udy, we show that PTEN plays a unique role in the insulin-signalling pathwa y in a breast cancer model, Ectopic expression of wild-type PTEN in MCF-7 e pithelial breast cancer cells resulted in universal inhibition of AM phosph orylation in response to stimulation by diverse growth factors and selectiv e inhibition of MEK/extracellular signal-regulated kinase (ERK) phosphoryla tion stimulated by insulin or insulin-like growth factor 1 (IGF-1), The tat ter was accompanied by a decrease in the phosphorylation of insulin recepto r substrate 1 (IRS-1) and the association of IRS-1 with Grb2/Sos, without a ffecting the phosphorylation status of the insulin receptor and Shc, nor Sh c/Grb2 complex formation, The MEK inhibitor, PD980059, but not the P13K inh ibitor, wortmannin, abolished the effect of PTEN on insulin-stimulated cell growth. Without addition of insulin, wortmannin reduced PTEN-mediated grow th suppression, whereas PD980059 had little effect, suggesting that PTEN su ppresses insulin-stimulated cell growth by blocking the mitogen-activated p rotein kinase (MAPK) pathway, Furthermore, PD980059 treatment led to the do wnregulation of cyclin D1 and the suppression of cell cycle progression. Ou r data suggest that PTEN blocks MAPK phosphorylation in response to insulin stimulation by inhibiting the phosphorylation of IRS-l and IRS-1/Grb2/Sos complex formation, which leads to downregulation of cyclin D1, inhibition o f cell cycle progression and suppression of cell growth.