A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration.
The strength and duration of mitogen-activated protein kinase (MAPK) signaling have been shown to regulate cell fate in different cell types. In this study, a general mechanism is described that explains how subtle differences in signaling kinetics are translated into a specific biological outcome. In fibroblasts, the expression of immediate early gene (IEG)-encoded Fos, Jun, Myc, and early growth response gene 1 (Egr-1) transcription factors is significantly extended by sustained extracellular signal-regulated kinase 1 and 2 (ERK1 and -2) signaling. Several of these proteins contain functional docking site for ERK, FXFP (DEF) domains that serve to locally concentrate the active kinase, thus showing that they can function as ERK sensors. Sustained ERK signaling regulates the posttranslational modifications of these IEG-encoded sensors, which contributes to their sustained expression during the G(1)-S transition. DEF domain-containing sensors can also interpret the small changes in ERK signal strength that arise from less than a threefold reduction in agonist concentration. As a result, downstream target gene expression and cell cycle progression are significantly changed.
Murphy
Leon O
LO
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
MacKeigan
Jeffrey P
JP
Blenis
John
J
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D051921:Fos-Related Antigen-2; D007700:Kinetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D041701:Swiss 3T3 Cells; D014157:Transcription Factors / Q000378:metabolism; D000099169:Fos-Related Antigen 1
D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; D020928:Mitogen-Activated Protein Kinases; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C497873:Fosl2 protein, mouse