Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt
Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt
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DOI：
10.1210/me.13.2.191
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发表时间：
1999-02-01
影响因子：
--
通讯作者：
Wierman, ME
中科院分区：
文献类型：
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作者：
Allen, MP;Zeng, C;Wierman, ME
我们确定了方舟，受体酪氨酸激酶Axl（Ufo，Tyro 7）的小鼠同源物，在一个屏幕上的新的因素参与GnRH神经元迁移，通过使用差异显示PCR的细胞系在两个窗口在GnRH神经元发育。方舟在GnRH神经元迁移时由嗅觉区肿瘤发育而来的Gn 10 GnRH细胞中表达，但在GnRH神经元迁移后由前脑肿瘤衍生而来的GT 1 -7细胞中不表达。由于方舟（Axl）信号保护成纤维细胞免于程序性细胞死亡，我们假设它可能在GnRH神经元中发挥抗凋亡作用。Gn 10（方舟阳性）GnRH细胞比GT 1 -7（方舟阴性）细胞更能抵抗血清戒断诱导的细胞凋亡，并且这种效应随着方舟（Axl）配体Gas 6的加入而增强。Gas 6/方舟刺激细胞外信号调节激酶，ERK，和丝氨酸-苏氨酸激酶，Akt，磷酸肌醇3-激酶（P13-K）途径的下游组分。为了确定Gas 6/方舟在GnRH神经元中的抗凋亡作用是否需要ERK或Akt活化，在Gas 6不存在或存在的情况下，在有或没有ERK和P13-K信号级联抑制剂的情况下，使细胞血清饥饿。Gas 6挽救了Gn 10细胞的凋亡，这种作用被细胞与促分裂原活化蛋白/ERK激酶（MEK）抑制剂PD 98059或渥曼青霉素（但不是雷帕霉素）共孵育所阻断。这些数据支持Gas 6/方舟信号通过ERK和P13-K（通过Akt）途径在保护GnRH神经元免于神经元迁移的程序性细胞死亡中的重要作用。
We identified Ark, the mouse homolog of the receptor tyrosine kinase Axl (Ufo, Tyro7), in a screen for novel factors involved in GnRH neuronal migration by using differential-display PCR on cell lines derived at two windows during GnRH neuronal development. Ark is expressed in Gn10 GnRH cells, developed from a tumor in the olfactory area when GnRH neurons are migrating, but not in GT1-7 cells, derived from a tumor in the forebrain when GnRH neurons are postmigratory. Since Ark (Axl) signaling protects from programmed cell death in fibroblasts, we hypothesized that it may play an antiapoptotic role in GnRH neurons. Gn10 (Ark positive) GnRH cells were more resistant to serum withdrawal-induced apoptosis than GT1-7 (Ark negative) cells, and this effect was augmented with the addition of Gas6, the Ark (Axl) ligand. Gas6/Ark stimulated the extracellular signal-regulated kinase, ERK, and the serine-threonine kinase, Akt, a downstream component of the phosphoinositide 3-kinase (Pl3-K) pathway. To determine whether ERK or Akt activation is required for the antiapoptotic effects of Gas6/Ark in GnRH neurons, cells were serum starved in the absence or presence of Gas6, with or without inhibitors of ERK and Pl3-K signaling cascades. Gas6 rescued Gn10 cells from apoptosis, and this effect was blocked by coincubation of the cells with the mitogen-activated protein/ERK kinase (MEK) inhibitor, PD98059, or wortmannin (but not rapamycin). These data support an important role for Gas6/Ark signaling via the ERK and P13-K (via Akt) pathways in the protection of GnRH neurons from programmed cell death across neuronal migration.