Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, CA 94720, USA.
Science. 2010 Mar 12;327(5971):1380-5. doi: 10.1126/science.1181729.
Activation of the EphA2 receptor tyrosine kinase by ephrin-A1 ligands presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer. We reconstituted this intermembrane signaling geometry between live EphA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EphA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EphA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease 10. Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines reveals characteristic differences that strongly correlate with invasion potential. These observations reveal a mechanism for spatio-mechanical regulation of EphA2 signaling pathways.
活 EphA2 表达的人乳腺癌细胞与支持侧向扩散 Ephrin-A1 的膜之间重建了这种跨膜信号几何形状。观察到了受体-配体结合、聚集以及随后在连接处的侧向运输。通过在基底上纳米制造物理障碍可以阻断 EphA2 的运输。这种 EphA2 的物理重排改变了细胞对 Ephrin-A1 的反应，如细胞骨架形态的变化和整联蛋白金属蛋白酶 10 的募集所观察到的那样。对 26 种乳腺上皮细胞系文库中受体-配体空间组织的定量分析揭示了与侵袭潜力强烈相关的特征差异。这些观察结果揭示了 EphA2 信号通路的空间机械调节机制。
