Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR, UK.
EMBO Rep. 2012 Aug;13(8):733-40. doi: 10.1038/embor.2012.92. Epub 2012 Jun 26.
We have recently described that autophagic targeting of Src maintains cancer cell viability when FAK signalling is defective. Here, we show that the Ret tyrosine kinase is also degraded by autophagy in cancer cells with altered/reduced FAK signalling, preventing its binding to FAK at integrin adhesions. Inhibition of autophagy restores Ret localization to focal adhesions. Importantly, Src kinase activity is required to target Ret to autophagosomes and enhance Ret degradation. Src is thus a general mediator of selective autophagic targeting of adhesion-linked kinases, and Ret a second FAK-binding tyrosine kinase degraded through autophagy in cancer cells under adhesion stress. Src--by controlling not only its own degradation but also that of other FAK-binding partners--allows cancer cell survival, suggesting a new therapeutic strategy.
我们最近描述了，当黏着斑激酶（FAK）信号通路缺陷时，自噬靶向Src 可以维持癌细胞的存活。在这里，我们发现，在黏着斑激酶信号通路改变/减少的癌细胞中，Ret 原癌基因酪氨酸激酶也会被自噬降解，从而阻止其在整合素黏附处与 FAK 结合。自噬的抑制会恢复 Ret 在粘着斑处的定位。重要的是，Src 激酶活性是将 Ret 靶向自噬体并增强 Ret 降解所必需的。因此，Src 是黏附连接激酶的选择性自噬靶向的一般介质，而 Ret 是在黏附应激下通过自噬在癌细胞中降解的第二个黏着斑激酶结合酪氨酸激酶。Src--通过控制不仅自身的降解，而且控制其他 FAK 结合伙伴的降解--允许癌细胞存活，这提示了一种新的治疗策略。
