MEK2 is sufficient but not necessary for proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells.

Abstract

Mitogen-activated protein kinase kinases (MKK or MEK) 1 and 2 are usually treated as redundant kinases. However, in assessing their relative contribution towards ERK-mediated biologic response investigators have relied on tests of necessity, not sufficiency. In response we developed a novel experimental model using lethal toxin (LeTx), an anthrax toxin-derived pan-MKK protease, and genetically engineered protease resistant MKK mutants (MKKcr) to test the sufficiency of MEK signaling in melanoma SK-MEL-28 cells. Surprisingly, ERK activity persisted in LeTx-treated cells expressing MEK2cr but not MEK1cr. Microarray analysis revealed non-overlapping downstream transcriptional targets of MEK1 and MEK2, and indicated a substantial rescue effect of MEK2cr on proliferation pathways. Furthermore, LeTx efficiently inhibited the cell proliferation and anchorage-independent growth of SK-MEL-28 cells expressing MKK1cr but not MEK2cr. These results indicate in SK-MEL-28 cells MEK1 and MEK2 signaling pathways are not redundant and interchangeable for cell proliferation. We conclude that in the absence of other MKK, MEK2 is sufficient for SK-MEL-28 cell proliferation. MEK1 conditionally compensates for loss of MEK2 only in the presence of other MKK.

• Authors: Chih-Shia Lee, Karl J Dykema, Danielle M Hawkins, David M Cherba, Craig P Webb, Kyle A Furge, Nicholas S Duesbery
• Journal: PloS one (PLoS One) Vol. 6 Issue 2 Pg. e17165 (Feb 18 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21365009 (Publication Type: Journal Article)

Chemical References

• Antigens, Bacterial
• Bacterial Toxins
• RNA, Small Interfering
• anthrax toxin
• MAP2K2 protein, human
• MAP Kinase Kinase 2

Topics

• Animals
• Antigens, Bacterial (metabolism, pharmacology)
• Bacterial Toxins (metabolism, pharmacology)
• CHO Cells
• Catalytic Domain (drug effects, genetics)
• Cell Adhesion (drug effects, genetics)
• Cell Proliferation (drug effects)
• Cluster Analysis
• Cricetinae
• Cricetulus
• Gene Expression Profiling
• Humans
• MAP Kinase Kinase 2 (antagonists & inhibitors, genetics, metabolism, physiology)
• Melanoma (genetics, pathology)
• Microarray Analysis
• Neoplasm Invasiveness
• Point Mutation (physiology)
• Protein Processing, Post-Translational (drug effects, genetics)
• RNA, Small Interfering (pharmacology)
• Signal Transduction (drug effects, genetics)
• Skin Neoplasms (genetics, pathology)
• Tumor Cells, Cultured