FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling.
We report that the Forkhead family of transcription factors, FKHRL1, FKHR and AFX are novel components of neurotrophin receptor signaling. NGF rapidly induced the phosphorylation of FKHRL1 in PC12 cells. This effect is mediated by high-affinity TrkA receptor as nerve growth factor (NGF) induced the phosphorylation of FKHRL1 only in TrkA expressing cells and not p75-expressing cells. Additional experiments with various kinase inhibitors, the transient expression of constitutively active and dominant-negative Akt, and in vitro kinase assay revealed that phosphatidylinositol-3 (PtdIns3)/Akt kinase mediated the actions of NGF. Similar data were obtained for brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in primary cortical cultured neurons. These findings demonstrate for the first time that the phosphorylation of the Forkhead family of transcription factors can be modulated by neurotrophins via Trk receptors and PtdIns3K/Akt kinase (but not MAP or S6p70 kinases) in neuronal and non-neuronal cells. Moreover, survival assays with the PtdIns3 kinase inhibitor LY294002, active and dominant-negative forms of Akt indicate that the phosphorylation of FKHRL1 plays a role in neurotrophins-mediated cell survival.
Zheng
Wen-Hua
WH
Douglas Hospital Research Center, Departments of Psychiatry, and Pharmacology and Therapeutics, McGill University, Montreal, Canada.
Kar
Satyabrata
S
Quirion
Rémi
R
D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006801:Humans; D051379:Mice; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020933:Neurotrophin 3 / Q000494:pharmacology; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D019208:Brain-Derived Neurotrophic Factor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D020932:Nerve Growth Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor; D014157:Transcription Factors; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C499515:FOXO3 protein, rat; C108803:FOXO4 protein, human; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; C074639:Foxo1 protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C073922:neurotrophin 4