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FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling
Author(s) -
Zheng WenHua,
Kar Satyabrata,
Quirion Rémi
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.0022-3042.2002.00783.x
Subject(s) - tropomyosin receptor kinase a , trk receptor , neurotrophin , protein kinase b , low affinity nerve growth factor receptor , biology , microbiology and biotechnology , nerve growth factor , phosphorylation , tropomyosin receptor kinase b , cancer research , neurotrophic factors , kinase , tropomyosin receptor kinase c , signal transduction , receptor , growth factor , biochemistry , platelet derived growth factor receptor
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.