EGFR transactivates RON to drive oncogenic crosstalk
- University of New Mexico, United States
Abstract
Crosstalk between different receptor tyrosine kinases (RTKs) is thought to drive oncogenic signaling and allow therapeutic escape. EGFR and RON are two such RTKs from different subfamilies, which engage in crosstalk through unknown mechanisms. We combined high-resolution imaging with biochemical and mutational studies to ask how EGFR and RON communicate. EGF stimulation promotes EGFR-dependent phosphorylation of RON, but ligand stimulation of RON does not trigger EGFR phosphorylation – arguing that crosstalk is unidirectional. Nanoscale imaging reveals association of EGFR and RON in common plasma membrane microdomains. Two-color single particle tracking captured formation of complexes between RON and EGF-bound EGFR. Our results further show that RON is a substrate for EGFR kinase, and that transactivation of RON requires formation of a signaling competent EGFR dimer. These results support a role for direct EGFR/RON interactions in propagating crosstalk, such that EGF-stimulated EGFR phosphorylates RON to activate RON-directed signaling.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Source data for the quantitative plots and gels have been provided.
Article and author information
Author details
Carolina Franco Nitta
Funding
National Institutes of Health (R35GM126934)
- Diane S Lidke
National Institutes of Health (R21GM132716)
- Keith Lidke
National Institutes of Health (New Mexico Spatiotemporal Modeling Center,P50GM085273)
- Bridget S Wilson
- Diane S Lidke
National Institutes of Health (UNM MARC Program,2T34GM008751)
- Justine M Keth
National Institutes of Health (ASERT-IRACDA,K12GM088021)
- Elton D Jhamba
National Institutes of Health (UNM Undergraduate Pipeline Network,P30CA118100)
- Justine M Keth
- Aubrey C Gibson
National Institutes of Health (R01CA248166)
- Diane S Lidke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Satyajit Mayor, Marine Biological Laboratory, United States
Version history
- Preprint posted: August 12, 2020 (view preprint)
- Received: October 2, 2020
- Accepted: November 24, 2021
- Accepted Manuscript published: November 25, 2021 (version 1)
- Version of Record published: December 8, 2021 (version 2)
Copyright
© 2021, Franco Nitta et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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EGFR transactivates RON to drive oncogenic crosstalk
eLife 10:e63678.
https://doi.org/10.7554/eLife.63678
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