Deconstructing Receptor Signaling with Chemically Nanopatterned Interfaces
UC - Berkeley, US
Keywords: Dip Pen Nanolithography, DPN, Chemically Nanopatterned Interfaces
Abstract:Communication between a cell and its environment is mediated through receptors present in its membrane. Receptor activity is modulated through clustering interactions that initiate cascades of biochemical signals. This has generated a need for developing bio-patterning approaches directed at deconstrucing the role of micro- or nanoscale clustering in biochemical signaling. To address this challenge, synthetic nanopatterned lipid membranes presenting ephrin-A1 ligand were used to activate the EphA2 receptor tyrosine kinase in live cells. Upon ligand-receptor binding, microclusters formed, coalesced, and subsequently underwent global reorganization into a multi-micron central assembly domain. This domain regulated protease recruitment, cytoskeletal organization, and receptor turnover. Importantly, domain structure and function could be manipulated and spatially “mutated” using nanopatterns that act as lipid diffusion barriers. Quantitative measurement of nano- and micro-clustering across a library of human breast cancer cell lines showed a strong correlation with the expression of a subset of genes and proteins and with reported invasion potentials. These results uncover a previously unknown mechanism of RTK signal regulation in cancer that functions solely through higher-order clustering events and identify potential effector molecules which may serve as targets to treat aggressive disease.