Zheng Wen-Hua, Kar Satyabrata, Quirion Rémi
Douglas Hospital Research Center, Departments of Psychiatry, and Pharmacology and Therapeutics, McGill University, Montreal, Canada.
J Neurochem. 2002 Mar;80(6):1049-61. doi: 10.1046/j.0022-3042.2002.00783.x.
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.
我们报告称，转录因子叉头家族（FKHRL1、FKHR和AFX）是神经营养因子受体信号传导的新组分。在PC12细胞中，神经生长因子（NGF）迅速诱导FKHRL1磷酸化。此效应由高亲和力的TrkA受体介导，因为神经生长因子（NGF）仅在表达TrkA的细胞而非表达p75的细胞中诱导FKHRL1磷酸化。使用各种激酶抑制剂、组成型活性和显性负性Akt的瞬时表达以及体外激酶测定的进一步实验表明，磷脂酰肌醇-3（PtdIns3）/Akt激酶介导了NGF的作用。在原代皮质培养神经元中，对于脑源性神经营养因子（BDNF）、神经营养因子-3（NT-3）和神经营养因子-4（NT-4）也获得了类似的数据。这些发现首次证明，在神经元和非神经元细胞中，神经营养因子可通过Trk受体和PtdIns3K/Akt激酶（而非MAP或S6p70激酶）调节转录因子叉头家族的磷酸化。此外，使用磷脂酰肌醇-3激酶抑制剂LY294002、活性和显性负性形式的Akt进行的存活测定表明，FKHRL1的磷酸化在神经营养因子介导的细胞存活中起作用。
