Ras-dependent regulation of c-Jun phosphorylation is mediated by the Ral guanine nucleotide exchange factor-Ral pathway.
The transcription factor c-Jun is critically involved in the regulation of proliferation and differentiation as well as cellular transformation induced by oncogenic Ras. The signal transduction pathways that couple Ras activation to c-Jun phosphorylation are still partially elusive. Here we show that an activated version of the Ras effector Rlf, a guanine nucleotide exchange factor (GEF) of the small GTPase Ral, can induce the phosphorylation of serines 63 and 73 of c-Jun. In addition, we show that growth factor-induced, Ras-mediated phosphorylation of c-Jun is abolished by inhibitory mutants of the RalGEF-Ral pathway. These results suggest that the RalGEF-Ral pathway plays a major role in Ras-dependent c-Jun phosphorylation. Ral-dependent regulation of c-Jun phosphorylation includes JNK, a still elusive JNKK, and possibly Src.
de Ruiter
N D
ND
Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
Wolthuis
R M
RM
van Dam
H
H
Burgering
B M
BM
Bos
J L
JL
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012694:Serine; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000378:metabolism; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D011720:Pyrazoles; D011743:Pyrimidines; C097542:RLF protein, human; C490805:Rgl2 protein, mouse; D014157:Transcription Factors; D020726:ral Guanine Nucleotide Exchange Factor; D012694:Serine; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020725:ral GTP-Binding Proteins; D018631:ras Proteins