Port Martha D, Laszlo George S, Nathanson Neil M
Department of Pharmacology, University of Washington, School of Medicine, Seattle, Washington, USA.
J Neurochem. 2008 Aug;106(4):1941-51. doi: 10.1111/j.1471-4159.2008.05535.x. Epub 2008 Jul 4.
The cytokines that signal through the leukemia inhibitory factor (LIF) receptor are members of the neuropoietic cytokine family and have varied and numerous roles in the nervous system. In this report, we have determined the effects of growth factor stimulation on LIF receptor (LIFR) expression and signal transduction in the human neuroblastoma cell line NBFL. We show here that stimulation of NBFL cells with either epidermal growth factor or fibroblast growth factor decreases the level of LIFR in an extracellular signal-regulated kinase (Erk)1/2-dependent manner and that this down-regulation is due to an increase in the apparent rate of lysosomal LIFR degradation. Growth factor-induced decreases in LIFR level inhibit both LIF-stimulated phosphorylation of signal transducers and activators of transcription 3 and LIFR-mediated gene induction. We also show that Ser1044 of LIFR, which we have previously shown to be phosphorylated by Erk1/2, is required for the inhibitory effects of growth factors. Neurons are exposed to varying combinations and concentrations of growth factors and cytokines that influence their growth, development, differentiation, and repair in vivo. These findings demonstrate that LIFR expression and signaling in neuroblastoma cells can be regulated by growth factors that are potent activators of the mitogen-activated protein kinase pathway, and thus illustrate a fundamental mechanism that underlies crosstalk between receptor tyrosine kinase and neuropoietic cytokine signaling pathways.
通过白血病抑制因子（LIF）受体发出信号的细胞因子是神经生成性细胞因子家族的成员，在神经系统中具有多样且众多的作用。在本报告中，我们确定了生长因子刺激对人神经母细胞瘤细胞系NBFL中LIF受体（LIFR）表达和信号转导的影响。我们在此表明，用表皮生长因子或成纤维细胞生长因子刺激NBFL细胞会以细胞外信号调节激酶（Erk）1/2依赖性方式降低LIFR水平，并且这种下调是由于溶酶体LIFR降解的表观速率增加所致。生长因子诱导的LIFR水平降低会抑制LIF刺激的信号转导和转录激活因子3的磷酸化以及LIFR介导的基因诱导。我们还表明，LIFR的Ser1044（我们先前已证明其被Erk1/2磷酸化）是生长因子发挥抑制作用所必需的。在体内，神经元会接触到影响其生长、发育、分化和修复的各种组合和浓度的生长因子和细胞因子。这些发现表明，神经母细胞瘤细胞中的LIFR表达和信号传导可受到有丝分裂原激活蛋白激酶途径的有效激活剂——生长因子的调节，从而阐明了受体酪氨酸激酶和神经生成性细胞因子信号通路之间相互作用的一个基本机制。
