Mek1 alters epidermal growth and differentiation.
The highly homologous kinases, Mek1 and Mek2, act downstream of Ras and Raf to activate extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases. In epidermis, Ras and Raf promote hyperplasia; however, they act on multiple Mek-independent effectors, and the extent to which Meks can mediate these effects is unknown. To address this, we expressed inducible Meks in transgenic murine and human epidermis. Both Mek1 and Mek2 triggered ERK phosphorylation. Only Mek1, however, recapitulated Ras/Raf effects in increasing proliferation and integrin expression while suppressing differentiation, which are impacts characteristic of epidermal neoplasia. Furthermore, a kinase-dead Mek1 mutant incapable of phosphorylating ERK proteins retained ability to mediate Mek1-driven epidermal proliferation. Mek1 is thus sufficient to promote the proliferative epithelial phenotype in a manner independent of intact kinase function.
Scholl
Florence A
FA
VA Palo Alto Healthcare System, Palo Alto, California 94305, USA.
Dumesic
Phillip A
PA
Khavari
Paul A
PA
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D006706:Homeostasis; D006801:Humans; D016023:Integrins / Q000096:biosynthesis; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012867:Skin / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology
D016023:Integrins; D013629:Tamoxifen; C016601:afimoxifene; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases