Pancreatic tumor cells with mutant K-ras suppress ERK activity by MEK-dependent induction of MAP kinase phosphatase-2.
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 ERK 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 ERK 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-2 (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.
Yip-Schneider
M T
MT
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, USA. myipschn@iupui.edu
Lin
A
A
Marshall
M S
MS
D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics*; D002460:Cell Line; D015536:Down-Regulation; D054637:Dual-Specificity Phosphatases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D054639:Mitogen-Activated Protein Kinase Phosphatases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014638:Vanadates / Q000494:pharmacology
D004791:Enzyme Inhibitors; D014638:Vanadates; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054648:Protein Phosphatase 2; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases; C094132:Dusp4 protein, rat; D017027:Protein Tyrosine Phosphatases