Latinis K M, Koretzky G A
Department of Immunology, University of Iowa, Iowa City 52242, USA.
Blood. 1996 Feb 1;87(3):871-5.
Stimulation through the Fas/APO-1 receptor results in apoptosis through an incompletely characterized signaling pathway. More is known regarding signal transduction events that occur after ligation of the T-cell antigen receptor (TCR). It has been shown that TCR stimulation requires both the membrane tyrosine phosphatase, CD45, and the Src-family kinase, Lck, to result in cellular activation. Although prior studies suggest a role for protein tyrosine kinases and phosphatases in Fas signaling, we report here that Fas ligation induces apoptosis in T cells deficient in either CD45 or Lck. Further, in normal and CD45- or Lck-deficient cell lines, Fas stimulation results in activation of Jun kinase (JNK), a proposed mediator of stress activation pathways. Previous studies have also demonstrated a role for endogenous ceramide release in Fas-mediated apoptosis. We show that stimulation with a synthetic ceramide analog results in JNK activation as well as apoptosis, suggesting ceramide release occurs proximal to JNK activation in Fas signaling. Our data suggest that although CD45 and Lck are not required for Fas signaling, JNK activation may play an important role transducing distal signals that lead to apoptosis after Fas ligation.
通过Fas/APO-1受体进行刺激会通过一条特征尚未完全明确的信号通路导致细胞凋亡。关于T细胞抗原受体（TCR）连接后发生的信号转导事件，人们了解得更多。已经表明，TCR刺激需要膜酪氨酸磷酸酶CD45和Src家族激酶Lck两者共同作用才能导致细胞活化。尽管先前的研究表明蛋白酪氨酸激酶和磷酸酶在Fas信号传导中起作用，但我们在此报告，Fas连接在缺乏CD45或Lck的T细胞中诱导细胞凋亡。此外，在正常以及缺乏CD45或Lck的细胞系中，Fas刺激导致Jun激酶（JNK）活化，JNK是应激激活途径的一种假定介质。先前的研究还证明内源性神经酰胺释放在Fas介导的细胞凋亡中起作用。我们表明，用合成神经酰胺类似物进行刺激会导致JNK活化以及细胞凋亡，这表明在Fas信号传导中神经酰胺释放在JNK活化近端发生。我们的数据表明，尽管Fas信号传导不需要CD45和Lck，但JNK活化可能在转导Fas连接后导致细胞凋亡的远端信号方面发挥重要作用。
