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.
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.
Monje
Paula
P
Oral and Pharyngeal Cancer Branch, National Institute of Dental Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-4330, USA.
Marinissen
Maria Julia
MJ
Gutkind
J Silvio
JS
D016475:3T3 Cells; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation
D006657:Histones; D010982:Platelet-Derived Growth Factor; D016760:Proto-Oncogene Proteins c-fos; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D005982:Glutathione Transferase; D017479:Receptors, Platelet-Derived Growth Factor; D020928:Mitogen-Activated Protein Kinases