FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells.
FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells.
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DOI：
10.1371/journal.pgen.1004262
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发表时间：
2014-03
期刊：
影响因子：
4.5
通讯作者：
Vidal M
中科院分区：
文献类型：
--
作者：
Macagno JP;Diaz Vera J;Yu Y;MacPherson I;Sandilands E;Palmer R;Norman JC;Frame M;Vidal M
受体酪氨酸激酶（RTK）和粘着斑激酶（FAK）调节多种信号传导途径，包括丝裂原活化蛋白（MAP）激酶途径。FAK与几种RTK相互作用，但对FAK如何调节其下游信号传导知之甚少。在这里，我们研究了FAK如何调节由RTK RET和EGFR过表达引起的信号传导。FAK通过破坏MAPK通路抑制果蝇上皮细胞RTK信号转导。在MDA-MB-231人乳腺癌细胞中也观察到这种调节，表明它是人类中的保守现象。机械地，FAK减少受体再循环进入质膜，这导致较低的MAPK活化。相反，增加受体的膜池增加MAPK途径信号传导。FAK被广泛认为是癌症生物学中的治疗靶点;然而，在某些情况下，它也具有肿瘤抑制特性。因此，这里描述的RTK/MAPK信号传导的FAK介导的负调节可能在设计RTK驱动的肿瘤的治疗策略中具有潜在的意义。由于它们在癌症中的失调和它们被小化合物抑制的潜力，酪氨酸激酶是癌症治疗考虑中的最重要的靶标之一。一种这样的致癌酪氨酸激酶是FAK，已知其在细胞表面调节整合素和受体酪氨酸激酶（RTK）下游的细胞信号传导。然而，在这项研究中，我们报道FAK可以作为致癌受体酪氨酸激酶的抑制剂。这种机制在体内果蝇组织和体外人类癌症衍生细胞中观察到，这也表明它是人类进化保守的机制。FAK通过抑制受体再循环至细胞表面来控制受体的亚细胞定位，从而介导这种抑制。这些结果表明，在某些特定的癌症背景下，如RTK驱动的肿瘤，FAK可能作为一种肿瘤抑制因子，因此，可能不是一个有效的药物靶点。
Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours. Due to their deregulation in cancer and their potential to be inhibited by small chemical compounds, tyrosine kinases are among the most important targets under consideration for cancer therapeutics. One such oncogenic tyrosine kinase is FAK, which is known to regulate cellular signalling downstream of Integrins and Receptor Tyrosine Kinases (RTK) at the cell surface. In this study, however, we report that FAK can act as a suppressor of oncogenic Receptor Tyrosine Kinases. This mechanism was observed in fruit fly tissues in vivo and human cancer-derived cells in vitro, which additionally suggests it is an evolutionary conserved mechanism in humans. FAK mediated this inhibition by controlling the sub-cellular localisation of receptors, via suppression of receptor recycling to the cell surface. These results suggest that in some particular cancer contexts such as RTK-driven tumours, FAK may act as a tumour suppressor and therefore, may not be a valid drug target.
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