PME-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma

Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway activity is regulated by the antagonist function of activating kinases and inactivating protein phosphatases. Sustained ERK pathway activity is commonly observed in human malignancies; however, the mechanisms by which the pathway is protected from phosphatase-mediated inactivation in the tumor tissue remain obscure. Here, we show that methyiesterase PME-I-mediated inhibi- tion of the protein phosphatase 2A promotes basal ERK pathway activity and is required for efficient growth factor response. Mechanistically, PME-I is shown to support ERK pathway signaling upstream of Raf, but downstream of growth factor receptors and protein kinase C. In malignant gliomas, PME-I expression levels correlate with both ERK activity and cell proliferation in vivo. Moreover, PME-I expression signif- icantly correlates with disease progression in human astro- cytic gliomas (n = 222). Together, these observations identify FME-I expression as one mechanism by which ERK pathway activity is maintained in cancer cells and suggest an important functional role for PME-I in the disease progression of human astrocytic gliomas.