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Molecular and Cellular Biology, November 2001, p. 7460-7469, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7460-7469.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Transcription Factor GATA4 Is Activated by Extracellular Signal-Regulated Kinase 1- and 2-Mediated Phosphorylation of Serine 105 in Cardiomyocytes

Qiangrong Liang,1 Russell J. Wiese,2 Orlando F. Bueno,1 Yan-Shan Dai,1,2 Bruce E. Markham,2 and Jeffery D. Molkentin1,*

Department of Pediatrics, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229-3039,1 and Department of Cell Biology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert, Ann Arbor, Michigan 481052

Received 21 May 2001/Returned for modification 22 June 2001/Accepted 7 August 2001

The zinc finger-containing transcription factor GATA4 has been implicated as a critical regulator of multiple cardiac-expressed genes as well as a regulator of inducible gene expression in response to hypertrophic stimulation. Here we demonstrate that GATA4 is itself regulated by the mitogen-activated protein kinase signaling cascade through direct phosphorylation. Site-directed mutagenesis and phospho-specific GATA4 antiserum revealed serine 105 as the primary site involved in agonist-induced phosphorylation of GATA4. Infection of cultured cardiomyocytes with an activated MEK1-expressing adenovirus induced robust phosphorylation of serine 105 in GATA4, while a dominant-negative MEK1-expressing adenovirus blocked agonist-induced phosphorylation of serine 105, implicating extracellular signal-regulated kinase (ERK) as a GATA4 kinase. Indeed, bacterially purified ERK2 protein directly phosphorylated purified GATA4 at serine 105 in vitro. Phosphorylation of serine 105 enhanced the transcriptional potency of GATA4, which was sensitive to U0126 (MEK1 inhibitor) but not SB202190 (p38 inhibitor). Phosphorylation of serine 105 also modestly enhanced the DNA binding activity of bacterially purified GATA4. Finally, induction of cardiomyocyte hypertrophy with an activated MEK1-expressing adenovirus was blocked with a dominant-negative GATA4-engrailed-expressing adenovirus. These results suggest a molecular pathway whereby MEK1-ERK1/2 signaling regulates cardiomyocyte hypertrophic growth through the transcription factor GATA4 by direct phosphorylation of serine 105, which enhances DNA binding and transcriptional activation.

* Corresponding author. Mailing address: Division of Molecular Cardiovascular Biology, Department of Pediatrics, Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Phone: (513) 636-3557. Fax: (513) 636-5958. E-mail: jeff.molkentin{at}chmcc.org.

Molecular and Cellular Biology, November 2001, p. 7460-7469, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7460-7469.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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