Sensed by a DEF Domain

Science's STKE  13 Aug 2002:
Vol. 2002, Issue 145, pp. tw293-TW293
DOI: 10.1126/stke.2002.145.tw293

How activation of one pathway, the mitogen-activated protein kinase (MAPK) ERK pathway, can stimulate such opposite cellular responses as proliferation or differentiation is one of the fundamental questions in cell biology (see Assoian). Murphy et al. suggest that the DEF domain in such immediate early gene products as Fos, Fra-1, Fra-1, Jun, Myc, and others may be a critical component to interpreting the transient or sustained activation of the ERK pathway. Analysis of the phosphorylation of c-Fos and mutants in positions Ser374 and Ser362 (the site phosphorylated by the kinases ERK and RSK) showed that phosphorylation of those two sites stimulated the phosphorylation of other residues (Thr325 and Thr331) by ERK. The ability of ERK to phosphorylate residues other than Ser374 depended on the integrity of an ERK-binding motif called DEF (amino acids F343TYP in c-Fos). Phosphorylation of Thr325 correlated with the stimulation of cell proliferation in response to sustained ERK signaling. Mutation of Thr325 and Thr331 or the DEF domain blocked the induction of transformation by c-Fos and inhibited AP-1-stimulated transcription. The authors propose the following model for how DEF-domain-containing proteins serve as ERK sensors. Growth factors stimulate immediate early gene transcription through the ERK pathway. If the signal is transient, then the gene products are unstable. If the ERK signal persists, then the initial phosphorylation of the proteins exposes the DEF domain, to which ERK binds and causes phosphorylation of other sites, stabilizing the protein.

R. K. Assoian, Common sense signalling. Nat. Cell Biol. 4, E187-E188 (2002). [Online Journal]

L. O. Murphy, S. Smith, R.-H. Chen, D. C. Finger, J. Blenis, Molecular interpretation of ERK signal duration by immediate early gene products. Nat. Cell Biol. 4, 556-564 (2002). [Online Journal]