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PMID: 12110590 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38.

The EMBO journal ·Vol. 21 ·No. 14 ·2002-07-15 ·Pages 3782-93

Ouwens DM, de Ruiter ND, van der Zon GC, Carter AP, Schouten J, van der Burgt C, Kooistra K, Bos JL, Maassen JA, van Dam H

Abstract

Transcription factor ATF2 regulates gene expression in response to environmental changes. Upon exposure to cellular stresses, the mitogen-activated proteinkinase (MAPK) cascades including SAPK/JNK and p38 can enhance ATF2's transactivating function through phosphorylation of Thr69 and Thr71. How ever, the mechanism of ATF2 activation by growth factors that are poor activators of JNK and p38 is still elusive. Here, we show that in fibroblasts, insulin, epidermal growth factor (EGF) and serum activate ATF2 via a so far unknown two-step mechanism involving two distinct Ras effector pathways: the Raf-MEK-ERK pathway induces phosphorylation of ATF2 Thr71, whereas subsequent ATF2 Thr69 phosphorylation requires the Ral-RalGDS-Src-p38 pathway. Cooperation between ERK and p38 was found to be essential for ATF2 activation by these mitogens; the activity of p38 and JNK/SAPK in growth factor-stimulated fibroblasts is insufficient to phosphorylate ATF2 Thr71 or Thr69 + 71 significantly by themselves, while ERK cannot dual phosphorylate ATF2 Thr69 + 71 efficiently. These results reveal a so far unknown mechanism by which distinct MAPK pathways and Ras effector pathways cooperate to activate a transcription factor.

MeSH Terms
Activating Transcription Factor 2 Blood Cell Line Cyclic AMP Response Element-Binding Protein/chemistry,metabolism Epidermal Growth Factor/physiology Humans Insulin/physiology MAP Kinase Signaling System Phosphorylation Threonine/metabolism Transcription Factors/chemistry,metabolism
Chemicals
ATF2 protein, human Activating Transcription Factor 2 Cyclic AMP Response Element-Binding Protein Insulin Transcription Factors Threonine Epidermal Growth Factor
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Ouwens D Margriet
Department of Molecular Cell Biology, Section of Signal Transduction, Leiden University Medical Centre, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.
de Ruiter Nancy D
van der Zon Gerard C M
Carter Andrew P
Schouten Jan
van der Burgt Corina
Kooistra Klaas
Bos Johannes L
Maassen J Antonie
van Dam Hans
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdf361
Published
2002-07-15
Pages
3782-93
Language
English
Region
England
NLM ID
8208664
PMCID
PMC126107
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/cdf361 PMC Full Text View journal details
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