title: 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.affiliation: Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
authors.forename: Chih-Shia
authors.initials: CS
authors.lastname: Lee
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Dykema
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Hawkins
authors.forename: David M
authors.initials: DM
authors.lastname: Cherba
authors.forename: Craig P
authors.initials: CP
authors.lastname: Webb
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Furge
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Duesbery
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism / Q000494:pharmacology; D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D020134:Catalytic Domain / Q000187:drug effects / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D006224:Cricetinae; D003412:Cricetulus; D020869:Gene Expression Profiling; D006801:Humans; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D046228:Microarray Analysis; D009361:Neoplasm Invasiveness; D017354:Point Mutation / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D034741:RNA, Small Interfering; C030325:anthrax toxin; C482128:MAP2K2 protein, human; D048370:MAP Kinase Kinase 2