p38 Mitogen-activated Protein Kinase Activation Is Required for Fibroblast Growth Factor-2-stimulated Cell Proliferation but Not Differentiation*
Abstract
Basic fibroblast growth factor (FGF-2) is a member of a family of polypeptides that have roles in a wide range of biological processes. To determine why different cell types show distinct responses to treatment with FGF-2, the array of FGF receptors present on the surface of a cell which differentiates in response to FGF-2 (PC12 cells) was compared with that present on the surface of a cell that proliferates in response to FGF-2 (Swiss 3T3 fibroblasts). Both cell types express exclusively FGFR1, suggesting that there are cell type-specific FGFR1 signaling pathways. Since mitogen-activated protein kinases function as mediators of cellular responses to a variety of stimuli, the roles of these proteins in FGF-mediated responses were examined. FGF-2 activates extracellular signal-regulated kinases with similar kinetics in both fibroblasts and PC12 cells, and a specific inhibitor of extracellular signal-regulated kinase activation blocks differentiation but has little effect on proliferation. In contrast, while p38 mitogen-activated protein kinase is activated weakly and transiently in PC12 cells treated with FGF-2, a much stronger and sustained activation of this kinase is seen in FGF-2-treated fibroblasts. Furthermore, specific inhibitors of this kinase block proliferation but have no effect on differentiation. This effect on proliferation is specific for FGF-2 since the same concentrations of inhibitors have little or no effect on proliferation induced by serum.
Footnotes
-
↵* This work was supported by National Institutes of Health Grant GM54604.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Abbreviations:
- FGF
-
fibroblast growth factor
- FGFR
-
fibroblast growth factor receptor
- MAP
-
mitogen-activated protein
- MAPK
-
mitogen-activated protein kinase
- SAPK
-
stress-activated protein kinase
- ERK
-
extracellular signal-regulated kinase
- ATF-2
-
activating transcription factor 2
- CREB
-
cAMP-responsive element-binding protein
- PAGE
-
polyacrylamide gel electrophoresis, PBS, phosphate-buffered saline
- TBS
-
Tris-buffered saline
- PMSF
-
phenylmethylsulfonyl fluoride
- DMEM
-
Dulbecco’s modified minimal essential medium
- PDGF
-
platelet-derived growth factor
- GST
-
glutathione S-transferase
- MAPKAP kinase-2
-
mitogen-activated protein kinase activated protein kinase-2
- MOPS
-
4-morpholinepropanesulfonic acid
- eIF4E
-
eukaryotic initiation factor-4E
-
- Received December 16, 1998.
- Revision received March 4, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
