c-Fos transcriptional activity stimulated by H-Ras-activated protein kinase distinct from JNK and ERK.
Ras proteins exert their mitogenic and oncogenic effects through activation of downstream protein kinases. An important question is how Ras-generated signals reach the nucleus to activate downstream target genes. AP-1, a heterodimeric complex of Jun and Fos proteins, which activates mitogen-inducible genes, is a major nuclear target of Ras. Ras can stimulate AP-1 activity by inducing c-fos transcription, a process which is probably mediated by the ERK1 and -2 mitogen-activated protein (MAP) kinases, which phosphorylate the transcription factor Elk-1/TCF. Besides inducing transcription from fos and jun genes, mitogens and Ras proteins enhance AP-1 activity through phosphorylation of c-Jun. Phosphorylation of the c-Jun activation domain leads to c-jun induction through an autoregulatory loop. Ras- and ultra-violet-responsive protein kinases that phosphorylate c-Jun on serine residues at positions 63 and 73 and stimulate its transcriptional activity have been identified. These proline-directed kinases, termed JNKs, are novel MAP kinases. It is not clear, however, whether c-Jun is the only recipient and JNK the only transducer of the Ras signal to AP-1 proteins. A short sequence surrounding the major JNK phosphorylation site of c-Jun is conserved in c-Fos and is part of its activation domain, suggesting that c-Fos may be similarly regulated. Here we show that Ras does indeed augment the transcriptional activity of c-Fos through phosphorylation at Thr 232, the homologue of Ser 73 of c-Jun. However, this is mediated by a novel Ras- and mitogen-responsive proline-directed protein kinase that is different from JNKs and ERKs. Therefore, at least three types of proline-directed kinases transmit Ras- and mitogen-generated signals to the transcriptional machinery.
Deng
T
T
Department of Pharmacology, University of California at San Diego School of Medicine, La Jolla 92093-0636.
Karin
M
M
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1; D010766:Phosphorylation / Q000528:radiation effects; D038461:Proline-Directed Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013912:Threonine / Q000378:metabolism; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; C494187:POU1F1 protein, human; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D013912:Threonine; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D038461:Proline-Directed Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D013755:Tetradecanoylphorbol Acetate