title: PME-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma.
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.
authors.affiliation: Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
authors.forename: Pietri
authors.initials: P
authors.lastname: Puustinen
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Junttila
authors.forename: Sari
authors.initials: S
authors.lastname: Vanhatupa
authors.forename: Anna A
authors.initials: AA
authors.lastname: Sablina
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Hector
authors.forename: Kaisa
authors.initials: K
authors.lastname: Teittinen
authors.forename: Olayinka
authors.initials: O
authors.lastname: Raheem
authors.forename: Kirsi
authors.initials: K
authors.lastname: Ketola
authors.forename: Shujun
authors.initials: S
authors.lastname: Lin
authors.forename: Juergen
authors.initials: J
authors.lastname: Kast
authors.forename: Hannu
authors.initials: H
authors.lastname: Haapasalo
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005354:Fibrosarcoma / Q000201:enzymology / Q000473:pathology; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D007930:Leucine / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008745:Methylation; D051379:Mice; D041681:NIH 3T3 Cells; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; D054648:Protein Phosphatase 2; D007930:Leucine