Ribosomal S6 kinase as a mediator of keratinocyte growth factor-induced activation of Akt in epithelial cells.
The keratinocyte growth factor receptor (KGFR) is a member of the fibroblast growth factor receptor (FGFR) superfamily. The proximal signaling molecules of FGFRs are much less characterized compared with other growth factor receptors. Using the yeast two-hybrid assay, we have identified ribosomal S6 kinase (RSK) to be a protein that associates with the cytoplasmic domain of the KGFR. The RSK family of kinases controls multiple cellular processes, and our studies for the first time show association between the KGFR and RSK. Using a lung-specific inducible transgenic system we have recently demonstrated protective effects of KGF on the lung epithelium and have demonstrated KGF-induced activation of the prosurvival Akt pathway both in vivo and in vitro. Here we show that a kinase inactive RSK mutant blocks KGF-induced Akt activation and KGF-mediated inhibition of caspase 3 activation in epithelial cells subjected to oxidative stress. It was recently shown that RSK2 recruits PDK1, the kinase responsible for both Akt and RSK activation. When viewed collectively, it appears that the association between the KGFR and RSK plays an important role in KGF-induced Akt activation and consequently in the protective effects of KGF on epithelial cells.
Pan
Zhong-Zong
ZZ
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Devaux
Yvan
Y
Ray
Prabir
P
D000818:Animals; D053148:Caspase 3; D061945:Caspase Inhibitors; D002460:Cell Line; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D014443:Tyrosine / Q000378:metabolism
D061945:Caspase Inhibitors; C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; D005419:Flavonoids; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011518:Proto-Oncogene Proteins; D017468:Receptors, Fibroblast Growth Factor; D051523:Fibroblast Growth Factor 7; D014443:Tyrosine; D005346:Fibroblast Growth Factors; D006861:Hydrogen Peroxide; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one