Cursi Silvia, Rufini Alessandra, Stagni Venturina, Condò Ivano, Matafora Vittoria, Bachi Angela, Bonifazi Antonio Paniccià, Coppola Luigi, Superti-Furga Giulio, Testi Roberto, Barilà Daniela
Department of Experimental Medicine and Biochemical Sciences, Dulbecco Telethon Institute, University of Rome Tor Vergata, Rome, Italy.
EMBO J. 2006 May 3;25(9):1895-905. doi: 10.1038/sj.emboj.7601085. Epub 2006 Apr 13.
We identified Caspase-8 as a new substrate for Src kinase. Phosphorylation occurs on Tyr380, situated in the linker region between the large and the small subunits of human Procaspase-8, and results in downregulation of Caspase-8 proapoptotic function. Src activation triggers Caspase-8 phosphorylation on Tyr380 and impairs Fas-induced apoptosis. Accordingly, Src failed to protect Caspase-8-defective human cells in which a Caspase-8-Y380F mutant is expressed from Fas-induced cell death. Remarkably, Src activation upon EGF-receptor stimulation triggers endogenous Caspase-8 phosphorylation and prevents Fas-induced apoptosis. Tyr380 is phosphorylated also in human colon cancers where Src is aberrantly activated. These data provide the first evidence for a direct role of tyrosine phosphorylation in the control of caspases and reveal a new mechanism through which tyrosine kinases inhibit apoptosis and participate in tumor progression.
我们确定半胱天冬酶-8是Src激酶的一种新底物。磷酸化发生在人半胱天冬酶-8大亚基和小亚基之间的连接区域中的酪氨酸380上，导致半胱天冬酶-8促凋亡功能下调。Src激活触发酪氨酸380上的半胱天冬酶-8磷酸化，并损害Fas诱导的细胞凋亡。因此，Src无法保护表达半胱天冬酶-8-Y380F突变体的半胱天冬酶-8缺陷型人类细胞免受Fas诱导的细胞死亡。值得注意的是，表皮生长因子受体刺激后Src激活触发内源性半胱天冬酶-8磷酸化，并阻止Fas诱导的细胞凋亡。在Src异常激活的人类结肠癌中，酪氨酸380也被磷酸化。这些数据为酪氨酸磷酸化在半胱天冬酶控制中的直接作用提供了首个证据，并揭示了酪氨酸激酶抑制细胞凋亡并参与肿瘤进展的新机制。
