Transcriptional activation and transformation by FosB protein require phosphorylation of the carboxyl-terminal activation domain.
The transcription factor AP-1, composed of Fos-Jun dimers, mediates some 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 activation domain. Here we show by mutational analysis that the FosB C-terminal domain has a proline-based motif that is essential for both of these functions. Phosphopeptide mapping experiments show that the C terminus of FosB is phosphorylated within a cluster of functionally redundant serine residues that is adjacent to this proline-based motif. Mutation of these serine residues to alanine severely reduces the ability of this region to function as an activation domain and inhibits the ability of FosB protein to function as a transforming protein. Several observations suggest that the kinase responsible for phosphorylation of these sites is distinct from the mitogen-activation protein kinases and stress-activated protein kinases. Our results show that transcriptional activation and neoplastic transformation by the FosB protein are dependent on phosphorylation within the C terminus. This form of control may provide a potential mechanism of signal integration at the level of a single transcription factor.
Skinner
M
M
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Qu
S
S
Moore
C
C
Wisdom
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R
D000595:Amino Acid Sequence; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004352:Drug Resistance, Microbial; D006801:Humans; D008969:Molecular Sequence Data; D010449:Peptide Mapping; D010766:Phosphorylation; D011392:Proline; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012694:Serine; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic
D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D012694:Serine; D011392:Proline; D017871:Calcium-Calmodulin-Dependent Protein Kinases