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 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.
Puustinen
Pietri
P
Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
Junttila
Melissa R
MR
Vanhatupa
Sari
S
Sablina
Anna A
AA
Hector
Melissa E
ME
Teittinen
Kaisa
K
Raheem
Olayinka
O
Ketola
Kirsi
K
Lin
Shujun
S
Kast
Juergen
J
Haapasalo
Hannu
H
Hahn
William C
WC
Westermarck
Jukka
J
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
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