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 o f the c-fos proto-oncogene has been characterized. Growth factor stimu lation of quiescent fibroblasts activates a protein kinase cascade tha t leads to the rapid and transient phosphorylation of the serum respon se factor (SRF), a regulator of c-fos transcription. The in vivo kinet ics of SRF phosphorylation and dephosphorylation parallel the activati on and subsequent repression of c-fos transcription, suggesting that t his phosphorylation event plays a critical role in the control of c-fo s expression. The ribosomal S6 kinase pp90rsk, a growth factor-inducib le kinase, phosphorylates SRF in vitro at serine 103, the site that be comes newly phosphorylated upon growth factor stimulation in vivo. Pho sphorylation of serine 103 significantly enhances the affinity and rat e with which SRF associates with its binding site, the serum response element, within the c-fos promoter. These results suggest a model in w hich the growth factor-induced phosphorylation of SRF at serine 103 co ntributes to the activation of c-fos transcription by facilitating the formation of an active transcription complex at the serum response el ement.