Restriction of receptor movement alters cellular response: physical force sensing by EphA2.
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.
Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, CA 94720, USA.
Khalid
K
Salaita
Pradeep M
PM
Nair
Rebecca S
RS
Petit
Richard M
RM
Neve
Debopriya
D
Das
Joe W
JW
Gray
Jay T
JT
Groves
D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D000205:Actomyosin / Q000502:physiology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D048430:Cell Shape; D003599:Cytoskeleton / Q000502:physiology / Q000648:ultrastructure; D036382:Ephrin-A1 / Q000737:chemistry* / Q000378:metabolism*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008024:Ligands; D008051:Lipid Bilayers; D040542:Mechanotransduction, Cellular; D008565:Membrane Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D036104:Receptor, EphA2 / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
C497483:CD44 protein, human; D036382:Ephrin-A1; D018960:Hyaluronan Receptors; D008024:Ligands; D008051:Lipid Bilayers; D008565:Membrane Proteins; D000205:Actomyosin; D036104:Receptor, EphA2; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human