Beatson Institute for Cancer Research, Glasgow, UK.
Cell Signal. 2010 May;22(5):848-56. doi: 10.1016/j.cellsig.2009.12.012. Epub 2010 Jan 14.
Bcr-Abl is the transforming principle underlying chronic myelogenous leukaemia (CML). Here, we use a functional interaction proteomics approach to map pathways by which Bcr-Abl regulates defined cellular processes. The results show that Bcr-Abl regulates the actin cytoskeleton and non-apoptotic membrane blebbing via a GADS/Slp-76/Nck1 adaptor protein pathway. The binding of GADS to Bcr-Abl requires Bcr-Abl tyrosine kinase activity and is sensitive to the Bcr-Abl inhibitor imatinib, while the GADS/Slp-76 and Slp-76/Nck interactions are tyrosine phosphorylation independent. All three adaptor proteins co-localize with cortical actin in membrane blebs. Downregulation of each adaptor protein disrupts the actin cytoskeleton and membrane blebbing in a similar fashion and similar to imatinib. These findings highlight the importance of protein interaction dependent adaptor protein pathways in oncogenic kinase signaling.
Bcr-Abl 是慢性髓性白血病（CML）的致癌原则。在这里，我们采用功能相互作用蛋白质组学的方法来绘制 Bcr-Abl 调控特定细胞过程的途径。结果表明，Bcr-Abl 通过 GADS/Slp-76/Nck1 衔接蛋白途径调节肌动蛋白细胞骨架和非凋亡性细胞膜起泡。GADS 与 Bcr-Abl 的结合需要 Bcr-Abl 酪氨酸激酶活性，并且对 Bcr-Abl 抑制剂伊马替尼敏感，而 GADS/Slp-76 和 Slp-76/Nck 的相互作用则不依赖于酪氨酸磷酸化。这三种衔接蛋白都与皮质肌动蛋白在细胞膜泡中共定位。每种衔接蛋白的下调都以类似于伊马替尼的方式破坏肌动蛋白细胞骨架和细胞膜起泡。这些发现强调了依赖于蛋白相互作用的衔接蛋白途径在致癌激酶信号转导中的重要性。
