Keratinocyte growth factor activates p38 MAPK to induce stress fibre formation in human prostate DU145 cells.
FGF7/Keratinocyte growth factor (KGF) regulates the differentiation and development of the prostate epithelium, while over-expression of FGF8 and FGF1 are implicated in carcinogenesis of the prostate. We tested the hypothesis that different members of the FGF family function through different signalling molecules. In prostate DU145 cells, both FGF1 and FGF2 activated ERK1/2 potently and p38 moderately. KGF was however most efficient in inducing p38 activities but had no effect on ERK1/2 function. JNK and STAT activities were not induced by FGFs in prostate cells. In vitro expression of the transcription factors Elk-1 and MEF2A (substrates for ERK1/2 and p38, respectively) for functional quantification, confirmed the pattern of FGF-induced MAPK activations in COS-7 cells. Furthermore, KGF was more efficient than FGF1 and FGF2 in inducing actin stress fibres, and the specific p38 inhibitor SB202190 completely abolished this in a dose-dependent manner. The MEK1/2 inhibitor, U0126, had no effect on FGF-induced stress fibre formation. This study demonstrates the selective activation of MAPK family members by FGFs resulting in activation of transcription factors and stress fibre formation. As multiple FGFs are over-expressed in human prostate cancer, characterization of the distinct signalling pathway by FGFs may reveal new specific targets for therapy.
Mehta
P B
PB
School of Surgical and Reproductive Sciences, The Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Robson
C N
CN
Neal
D E
DE
Leung
H Y
HY
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D019556:COS Cells; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D002070:Butadienes; D004791:Enzyme Inhibitors; C496453:FGF7 protein, human; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; D014157:Transcription Factors; C113580:U 0126; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole