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

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

^* To whom correspondence should be addressed. E-mail: jukwes{at}utu.fi.

	Abstract

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):OF1–8]

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