Differing src signaling levels have distinct outcomes in drosophila
Differing src signaling levels have distinct outcomes in drosophila
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DOI：
10.1158/0008-5472.can-07-1376
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发表时间：
2007-11-01
期刊：
影响因子：
11.2
通讯作者：
Cagan, Ross L.
中科院分区：
文献类型：
--
作者：
Vidal, Marcos;Warner, Stephen;Cagan, Ross L.
在广泛的癌症中发现了高水平的Src活性。Src及其负调节因子Csk的作用已被广泛研究，尽管结果经常被证明是相互矛盾的，或者与整个生物体的相关性尚不清楚。在果蝇中，Src同源物的过表达导致凋亡细胞死亡，但矛盾的是，降低dCsk活性导致过度增殖和组织过度生长。本研究表明，在果蝇原位上皮中，Src信号的水平决定了Src激活的细胞结果。高Src信号水平特异性触发凋亡细胞死亡；低水平的抗凋亡信号同时促进细胞增殖。此外，我们的数据表明，激酶死亡的Src亚型的表达不一定是主要的负性因素，而是可以增加Src途径的活性，最有可能的是通过滴定Csk活性远离内源性Src。当我们检查Src和Ras之间的致癌合作时，我们强调了Src活性水平的重要性：当达到高Src信号水平时，可以观察到恶性过度生长。我们提出了一个模型，在肿瘤发生的早期阶段，低水平的Src信号促进存活和增殖，而在肿瘤晚期，强Src信号与抗凋亡信号结合，指导侵袭性迁移和转移。
High levels of Src activity are found in a broad spectrum of cancers. The roles of Src and its negative regulator Csk have been extensively studied, although results have often proved contradictory or the relevance to whole organisms is unclear. In Drosophila, overexpression of either Src orthologue resulted in apoptotic cell death, but paradoxically, reducing dCsk activity led to over-proliferation and tissue overgrowth. Here, we show that in Drosophila epithelia in situ, the levels of Src signaling determine the cellular outcome of Src activation. Apoptotic cell death was triggered specifically at high Src signaling levels; lower levels directed antiapoptotic signals while promoting proliferation. Furthermore, our data indicate that expression of kinase-dead Src isoforms do not necessarily act as dominant-negative factors, but can instead increase Src pathway activity, most likely by titrating Csk activity away from endogenous Src. The importance of Src activity levels was emphasized when we examined oncogenic cooperation between Src and Ras: malignant overgrowth was observed specifically when high Src signaling levels were achieved. We propose a model in which low levels of Src signaling promote survival and proliferation during early stages of tumorigenesis, whereas strong Src signaling, coupled with antiapoptotic signals, directs invasive migration and metastasis during advanced tumor stages.