Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2

• Published in: Science (American Association for the Advancement of Science) Vol. 327; no. 5971; pp. 1380 - 1385
• Main Authors: Salaita, Khalid, Nair, Pradeep M, Petit, Rebecca S, Neve, Richard M, Das, Debopriya, Gray, Joe W, Groves, Jay T
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 12-03-2010; The American Association for the Advancement of Science
• Subjects: Actins; Actomyosin - physiology; ADAM Proteins - metabolism; ADAM10 Protein; Amyloid Precursor Protein Secretases - metabolism; Artificial cells; Binding sites; Biological and medical sciences; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell adhesion; Cell Line, Tumor; Cell lines; Cell Membrane - metabolism; Cell membranes; Cell Shape; Cell surface receptors; Cellular biology; Cytoskeleton - physiology; Cytoskeleton - ultrastructure; Dissemination; Ephrin-A1 - chemistry; Ephrin-A1 - metabolism; Female; Humans; Hyaluronan Receptors - metabolism; Kinases; Ligands; Lipid Bilayers; Mechanotransduction, Cellular; Medical sciences; Membrane Proteins - metabolism; Nanostructured materials; Neoplasm Invasiveness; P branes; Protein Binding; Protein Multimerization; Protein Transport; Receptor, EphA2 - chemistry; Receptor, EphA2 - metabolism; Receptors; Signal Transduction; Tumor cell; Tumors; Human; Cancerology; Signaling pathway; trk receptor; Metastasis; Malignant tumor; Invasion; Cancer; Spatial organization; Biological receptor
• ISSN: 0036-8075; 1095-9203
• 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.