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Molecular and Cellular Biology, January 2004, p. 144-153, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.144-153.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Network of Immediate Early Gene Products Propagates Subtle Differences in Mitogen-Activated Protein Kinase Signal Amplitude and Duration

Leon O. Murphy, Jeffrey P. MacKeigan, and John Blenis*

Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Received 18 July 2003/ Returned for modification 4 September 2003/ Accepted 6 October 2003

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 G1-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.

* Corresponding author. Mailing address: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115. Phone: (617) 432-4848. Fax: (617) 432-1144. E-mail: jblenis{at}hms.harvard.edu.

Molecular and Cellular Biology, January 2004, p. 144-153, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.144-153.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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