Basic fibroblast growth factor-induced activation of novel CREB kinase during the differentiation of immortalized hippocampal cells.
Growth factors bind to their specific receptors on the responsive cell surface and thereby initiate dramatic changes in the proliferation, differentiation, and survival of their target cells. In the present study we have examined the mechanism by which growth factor-induced signals are propagated to the nucleus, leading to the activation of transcription factor, cis-acting cAMP response element (CRE)-binding protein (CREB), in immortalized hippocampal progenitor cells (H19-7). During the differentiation of H19-7 cells by basic fibroblast growth factor (bFGF) a critical regulatory Ser(133) residue of CREB was phosphorylated followed by an increase of CRE-mediated gene transcription. Expression of S133A CREB mutants blocked the differentiation of H19-7 cells by bFGF. Although the kinetics of CREB phosphorylation by EGF was transient, bFGF induced a prolonged pattern of CREB phosphorylation. Interestingly, bFGF-induced CREB phosphorylation and subsequent CRE-mediated gene transcription is not likely to be mediated by any of previously known signaling pathways that lead to phosphorylation of CREB, such as mitogen-activated protein kinases, protein kinase A, protein kinase C, phosphatidylinositol 3-kinase-p70(S6K), calcium/calmodulin dependent protein kinase, and casein kinase 2. By using in vitro in gel kinase assay the presence of a novel 120-kDa bFGF-inducible CREB kinase was identified. These findings identify a new growth factor-activated signaling pathway that regulates gene expression at the CRE.
Department of Pharmacology, Brain Research Institute, and Brain Korea 21 Projects for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
J Y
JY
Sung
S W
SW
Shin
Y S
YS
Ahn
K C
KC
Chung
D000818:Animals; D015153:Blotting, Western; D050882:CREB-Binding Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D047390:Casein Kinase II; D002454:Cell Differentiation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005799:Genes, Dominant; D005982:Glutathione Transferase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D002147:Calmodulin; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D016222:Fibroblast Growth Factor 2; D012694:Serine; D008156:Luciferases; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D005982:Glutathione Transferase; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases