Pancreatic tumor cells with mutant K-ras suppress ERK activity by MEK-dependent induction of MAP kinase phosphatase-2
Pancreatic tumor cells with mutant K-ras suppress ERK activity by MEK-dependent induction of MAP kinase phosphatase-2
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DOI：
10.1006/bbrc.2001.4243
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发表时间：
2001-02-02
影响因子：
3.1
通讯作者：
Marshall, MS
中科院分区：
文献类型：
--
作者：
Yip-Schneider, MT;Lin, A;Marshall, MS
K-ras基因的激活突变在人类胰腺癌中发生的比例很高。我们之前报道过，在人胰腺癌细胞系中存在致癌的、活化的K-ras不会导致细胞外信号调节激酶（ERK1和ERK2）的组成性激活。在本研究中，我们进一步对胰腺肿瘤细胞系中的EBB信号通路进行了表征，以确定ERK通路是否存在代偿性下调。我们发现血清诱导的ERK活化的衰减不是由于ERK磷酸化动力学的延迟，酪氨酸磷酸酶抑制剂正钒酸盐处理增加了ERR磷酸化水平，暗示钒酸盐敏感的酪氨酸磷酸酶在ERK的负调控中。此外，一种能够使ERK失活的双特异性磷酸酶，即丝裂原活化蛋白（MAP）激酶磷酸酶a （MKP-2）的表达在大多数胰腺肿瘤细胞系中升高，并与活性MAP激酶（MEK）的存在相关。综上所述，这些结果表明，表达致癌性K-ras的胰腺肿瘤细胞部分通过上调MKP-2的表达来抑制ERK信号通路进行补偿。(C) 2001学术出版社。
Activating mutations within the K-ras gene occur in a high percentage of human pancreatic carcinomas. We reported previously that the presence of oncogenic, activated K-ras in human pancreatic carcinoma cell lines did not result in constitutive activation of the extracellular signal-regulated kinases (ERK1 and ERK2). in the present, study, we further characterized the EBB signaling pathway in pancreatic tumor cell lines in order to determine whether the ERK pathway is subject to a compensatory downregulation. We found that the attenuation of serum-induced ERK activation was not due to a delay in the kinetics of ERK phosphorylation, Treatment with the tyrosine phosphatase inhibitor orthovanadate increased the level of ERR phosphorylation, implicating a vanadate-sensitive tyrosine phosphatase in the negative regulation of ERK. Furthermore, expression of a dual specificity phosphatase capable of inactivating ERK known as mitogen-activated protein (MAP) kinase phosphatase-a (MKP-2) was elevated in most of the pancreatic tumor cell lines and correlated with the presence of active MAP kinase kinase (MEK). Taken together, these results suggest that pancreatic tumor cells expressing oncogenic K-ras compensate, in part, by upregulating the expression of MKP-2 to repress the ERK signaling pathway. (C) 2001 Academic Press.