TRANSCRIPTIONAL ACTIVATION AND TRANSFORMATION BY FOSB PROTEIN REQUIREPHOSPHORYLATION OF THE CARBOXYL-TERMINAL ACTIVATION DOMAIN

The transcription factor AP-I, composed of Fos-Jun dimers, mediates so me aspects of the cellular response to growth factors. Transcriptional activation and neoplastic transformation by FosB, a member of the Fos family of proteins, require the presence of a potent C-terminal activ ation domain. Here we show by mutational analysis that the FosB C-term inal domain has a proline-based motif that is essential for both of th ese functions. Phosphopeptide mapping experiments show that the C term inus of FosB is phosphorylated within a cluster of functionally redund ant serine residues that is adjacent to this proline-based motif. Muta tion of these serine residues to alanine severely reduces the ability of this region to function as an activation domain and inhibits the ab ility of FosB protein to function as a transforming protein. Several o bservations suggest that the kinase responsible for phosphorylation of these sites is distinct from the mitogen-activation protein kinases a nd stress-activated protein kinases. Our results show that transcripti onal activation and neoplastic transformation by the FosB protein are dependent on phosphorylation within the C terminus. This form of contr ol may provide a potential mechanism of signal integration at the leve l of a single transcription factor.