Puustinen Pietri, Junttila Melissa R, Vanhatupa Sari, Sablina Anna A, Hector Melissa E, Teittinen Kaisa, Raheem Olayinka, Ketola Kirsi, Lin Shujun, Kast Juergen, Haapasalo Hannu, Hahn William C, Westermarck Jukka
Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
Cancer Res. 2009 Apr 1;69(7):2870-7. doi: 10.1158/0008-5472.CAN-08-2760. Epub 2009 Mar 17.
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.
细胞外信号调节激酶（ERK）/丝裂原活化蛋白激酶途径的活性受激活激酶和失活蛋白磷酸酶的拮抗作用调节。ERK途径的持续活性在人类恶性肿瘤中普遍存在；然而，该途径在肿瘤组织中免受磷酸酶介导的失活的机制仍不清楚。在这里，我们表明甲基酯酶PME-1介导的对蛋白磷酸酶2A的抑制促进了基础ERK途径的活性，并且是有效生长因子反应所必需的。从机制上讲，PME-1被证明在Raf上游支持ERK途径信号传导，但在生长因子受体和蛋白激酶C下游。在恶性胶质瘤中，PME-1表达水平与体内ERK活性和细胞增殖均相关。此外，PME-1表达与人星形胶质细胞瘤（n = 222）的疾病进展显著相关。总之，这些观察结果确定PME-1表达是癌细胞中维持ERK途径活性的一种机制，并表明PME-1在人类星形胶质细胞瘤的疾病进展中具有重要的功能作用。
