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Sci Rep. 2017 Sep 22;7(1):12150. doi: 10.1038/s41598-017-12257-y.

Multiplexed Exchange-PAINT imaging reveals ligand-dependent EGFR and Met interactions in the plasma membrane.

Author information

1
HMS LINCS Center, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
2
Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA.
3
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
4
Max Planck Institute of Biochemistry and LMU, Munich, Germany.
5
Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA. Peng_Yin@hms.harvard.edu.
6
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA. Peng_Yin@hms.harvard.edu.
7
Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. Gaudenz.Danuser@utsouthwestern.edu.
8
Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, 75390, USA. Gaudenz.Danuser@utsouthwestern.edu.
9
HMS LINCS Center, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA. peter_sorger@hms.harvard.edu.

Abstract

Signal transduction by receptor tyrosine kinases (RTKs) involves complex ligand- and time-dependent changes in conformation and modification state. High resolution structures are available for individual receptors dimers, but less is known about receptor clusters that form in plasma membranes composed of many different RTKs with the potential to interact. We report the use of multiplexed super-resolution imaging (Exchange-PAINT) followed by mean-shift clustering and random forest analysis to measure the precise distributions of five receptor tyrosine kinases (RTKs) from the ErbB, IGF-1R and Met families in breast cancer cells. We find that these receptors are intermixed nonhomogenously on the plasma membrane. Stimulation by EGF does not appear to induce a change in the density of EGFR in local clusters but instead results in formation of EGFR-Met and EGFR-ErbB3 associations; non-canonical EGFR-Met interactions are implicated in resistance to anti-cancer drugs but have not been previously detected in drug-naïve cells.

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