Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation
Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation
复制标题
DOI：
10.1038/sj.onc.1201419
复制
发表时间：
1997-11-13
期刊：
影响因子：
8
通讯作者：
Basilico, C
中科院分区：
文献类型：
--
作者：
Bellosta, P;Zhang, Q;Basilico, C
ARK (AXL) 是一个独特的受体酪氨酸激酶家族的原型，其胞外结构域中含有让人想起细胞粘附分子的特征，ARK 能够进行同种结合，从而导致一定程度的受体激活，但也可以被异嗜性配体 Gas6 激活，Gas6 是维生素 K 依赖性蛋白家族的成员，优先在静止细胞中表达。由于许多组织和细胞系同时表达 ARK 和 Gas6，因此我们研究了内源性和外源性 Gas6 对 ARK 表达细胞表型的影响，在这里，我们表明，在不自发表达该蛋白的 NIH3T3 细胞系中，Gas6 的组成型表达不会导致细胞转化或不受控制的生长，但可以防止血清剥夺诱导的细胞凋亡。重组外源 Gas6 还能够保护细胞免于凋亡，其浓度不会导致 DNA 合成的显着诱导、ARK 磷酸化的激活以及 MAP 激酶活性的微弱但显着的诱导，伴随着用 Gas6 处理的细胞存活率的增加。 ARK 信号传导的抗凋亡作用通过使用 ARK 敲除小鼠的成纤维细胞进行的研究得到证实，该研究表明，ARK 的缺失导致血清剥夺诱导的细胞凋亡水平升高，而添加 Gas6 无法挽救这种细胞凋亡。有趣的是，ARK 信号传导可以防止血清剥夺、myc 过表达或 TNF α 诱导的细胞凋亡，但不能防止紫外线诱导的细胞凋亡。辐射或星形孢菌素。这些结果表明 Gas6-ARK 信号传导的主要功能是在不允许细胞增殖的条件下提高细胞存活率。
ARK (AXL) is the prototype of a distinctive family of receptor tyrosine kinases which contain in their extracellular domains features reminiscent of cell adhesion molecules, ARK is capable of homophilic binding, which results in a degree of receptor activation, but can also be activated by a heterophilic ligand, Gas6, a member of the family of vitamin K dependent proteins that is preferentially expressed in quiescent cells, Since a number of tissues and cell lines express both ARK and Gas6, we studied the effect of endogenous and exogenous Gas6 on the phenotype of ARK expressing cells, Here we show that constitutive expression of Gas6 in an NIH3T3 cell line that does not spontaneously express this protein does not result in cell transformation or uncontrolled growth, but protects from apoptosis induced by serum deprivation. Recombinant exogenous Gas6 was also capable of protecting cells from apoptosis at concentrations that did not result in significant induction of DNA synthesis, Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. The antiapoptotic effect of ARK signaling was confirmed by studies using fibroblasts from ARK knock-out mice, that showed that the absence of ARK resulted in higher levels of serum deprivation-induced apoptosis, that could not be rescued by the addition of Gas6, Interestingly ARK signaling protects from apoptosis induced by serum deprivation, myc overexpression, or by TNF alpha but not from u.v. irradiation or Staurosporine. These results suggest that a major function of Gas6-ARK signaling is that of increasing cell survival under conditions which do not allow cell proliferation.