A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity.
A signaling pathway by which growth factors may induce transcription of the c-fos proto-oncogene has been characterized. Growth factor stimulation of quiescent fibroblasts activates a protein kinase cascade that leads to the rapid and transient phosphorylation of the serum response factor (SRF), a regulator of c-fos transcription. The in vivo kinetics of SRF phosphorylation and dephosphorylation parallel the activation and subsequent repression of c-fos transcription, suggesting that this phosphorylation event plays a critical role in the control of c-fos expression. The ribosomal S6 kinase pp90rsk, a growth factor-inducible kinase, phosphorylates SRF in vitro at serine 103, the site that becomes newly phosphorylated upon growth factor stimulation in vivo. Phosphorylation of serine 103 significantly enhances the affinity and rate with which SRF associates with its binding site, the serum response element, within the c-fos promoter. These results suggest a model in which the growth factor-induced phosphorylation of SRF at serine 103 contributes to the activation of c-fos transcription by facilitating the formation of an active transcription complex at the serum response element.
Rivera
V M
VM
Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115.
Miranti
C K
CK
Misra
R P
RP
Ginty
D D
DD
Chen
R H
RH
Blenis
J
J
Greenberg
M E
ME
D016475:3T3 Cells; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004247:DNA; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D038601:Ribosomal Protein S6; D019893:Ribosomal Protein S6 Kinases; D012269:Ribosomal Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D026362:Serum Response Factor; D015398:Signal Transduction; D015533:Transcriptional Activation
D000906:Antibodies; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; D026362:Serum Response Factor; D012694:Serine; D004815:Epidermal Growth Factor; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases