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Molecular and Cellular Biology, October 2003, p. 7030-7043, Vol. 23, No. 19
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.19.7030-7043.2003

Phosphorylation of the Carboxyl-Terminal Transactivation Domain of c-Fos by Extracellular Signal-Regulated Kinase Mediates the Transcriptional Activation of AP-1 and Cellular Transformation Induced by Platelet-Derived Growth Factor

Paula Monje, Maria Julia Marinissen, and J. Silvio Gutkind*

Oral and Pharyngeal Cancer Branch, National Institute of Dental Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-4330

Received 5 February 2003/ Returned for modification 8 April 2003/ Accepted 24 June 2003

Polypeptide growth factors, such as platelet-derived growth factor (PDGF), promote the reinitiation of DNA synthesis and cell growth through multiple intracellular signaling pathways that converge in the nucleus to regulate the activity of transcription factors, thereby controlling the expression of growth-promoting genes. Among them, the AP-1 (activating protein-1) family of transcription factors, including c-Fos and c-Jun family members, plays a key role, as AP-1 activity is potently activated by PDGF and is required to stimulate cell proliferation. However, the nature of the pathways connecting PDGF receptors to AP-1 is still poorly defined. In this study, we show that PDGF regulates AP-1 by stimulating the expression and function of c-Fos through extracellular signal-regulated kinase (ERK). The latter involves the direct phosphorylation by ERK of multiple residues in the carboxyl-terminal transactivation domain of c-Fos, which results in its increased transcriptional activity. Interestingly, the phosphorylation of c-Fos by ERK was required for the ability of PDGF and serum to stimulate the activity of c-Fos as well as AP-1-dependent transcription. Furthermore, we provide evidence that the ERK-dependent activation of c-Fos is an integral component of the mitogenic pathway by which PDGF regulates normal and aberrant cell growth.

* Corresponding author. Mailing address: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Building 30, Room 212, Bethesda, MD 20892-4340. Phone: (301) 496-6259. Fax: (301) 402-0823. E-mail: sg39v{at}nih.gov.

Molecular and Cellular Biology, October 2003, p. 7030-7043, Vol. 23, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.19.7030-7043.2003




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