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PME-1 Protects Extracellular Signal-Regulated Kinase Pathway Activity from Protein Phosphatase 2A–Mediated Inactivation in Human Malignant Glioma

¹ Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; ² Institute of Medical Technology and ³ Department of Pathology, University of Tampere; ⁴ Center for Laboratory Medicine and ⁵ Department of Pathology, Tampere University Hospital, Tampere, Finland; ⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; and ⁷ Biomedical Research Center, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Jukka Westermarck, University of Tampere, Biokatu 6-8, 33200 Tampere, Finland. Phone: 358407423007; Fax: 358335517029; E-mail: jukwes{at}utu.fi.

Key Words: PP2A • PPME-1 • Ras/Raf/MEK/ERK • malignant glioblastoma • tumor suppressor

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 methylesterase PME-1–mediated inhibition of the protein phosphatase 2A promotes basal ERK pathway activity and is required for efficient growth factor response. Mechanistically, PME-1 is shown to support ERK pathway signaling upstream of Raf, but downstream of growth factor receptors and protein kinase C. In malignant gliomas, PME-1 expression levels correlate with both ERK activity and cell proliferation in vivo. Moreover, PME-1 expression significantly correlates with disease progression in human astrocytic gliomas (n = 222). Together, these observations identify PME-1 expression as one mechanism by which ERK pathway activity is maintained in cancer cells and suggest an important functional role for PME-1 in the disease progression of human astrocytic gliomas. [Cancer Res 2009;69(7):2870–7]