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EGFR transactivates RON to drive oncogenic crosstalk

Carolina Franco Nitta, Ellen W. Green, Elton D. Jhamba, Justine M. Keth, Iraís Ortiz-Caraveo, Rachel M. Grattan, David J. Schodt, Aubrey C. Gibson, Ashwani Rajput, Keith A. Lidke, Mara P. Steinkamp, Bridget S. Wilson, Diane S. Lidke
doi: https://doi.org/10.1101/2020.08.11.246785
Carolina Franco Nitta
1Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
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Ellen W. Green
1Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
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Elton D. Jhamba
1Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
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Justine M. Keth
1Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
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Iraís Ortiz-Caraveo
1Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
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Rachel M. Grattan
1Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
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David J. Schodt
4Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131, USA
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Aubrey C. Gibson
1Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
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Ashwani Rajput
2Department of Surgery, University of New Mexico, Albuquerque, NM 87131, USA
3Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
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Keith A. Lidke
3Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
4Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131, USA
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Mara P. Steinkamp
1Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
3Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
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Bridget S. Wilson
1Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
3Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
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Diane S. Lidke
1Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
3Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
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  • For correspondence: dlidke@salud.unm.edu
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Abstract

SUMMARY Crosstalk between disparate membrane receptors is thought to drive oncogenic signaling and allow for therapeutic resistance. EGFR and RON are members of two unique receptor tyrosine kinase (RTK) subfamilies that engage in crosstalk through unknown mechanisms. We combined high resolution imaging with biochemical studies and structural mutants to understand how EGFR and RON communicate. We found that EGF stimulation results in EGFR-dependent RON phosphorylation. Crosstalk is unidirectional, since MSP stimulation of RON does not trigger EGFR phosphorylation. Two-color single particle tracking captured the formation of complexes between RON and EGFR, supporting a role for direct interactions in propagating crosstalk. We further show that RON is a substrate for EGFR kinase, and transactivation of RON requires the formation of a signaling competent EGFR dimer. These results identify critical structural features of EGFR/RON crosstalk and provide new mechanistic insights into therapeutic resistance.

Competing Interest Statement

The authors have declared no competing interest.

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Posted August 12, 2020.
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EGFR transactivates RON to drive oncogenic crosstalk
Carolina Franco Nitta, Ellen W. Green, Elton D. Jhamba, Justine M. Keth, Iraís Ortiz-Caraveo, Rachel M. Grattan, David J. Schodt, Aubrey C. Gibson, Ashwani Rajput, Keith A. Lidke, Mara P. Steinkamp, Bridget S. Wilson, Diane S. Lidke
bioRxiv 2020.08.11.246785; doi: https://doi.org/10.1101/2020.08.11.246785
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EGFR transactivates RON to drive oncogenic crosstalk
Carolina Franco Nitta, Ellen W. Green, Elton D. Jhamba, Justine M. Keth, Iraís Ortiz-Caraveo, Rachel M. Grattan, David J. Schodt, Aubrey C. Gibson, Ashwani Rajput, Keith A. Lidke, Mara P. Steinkamp, Bridget S. Wilson, Diane S. Lidke
bioRxiv 2020.08.11.246785; doi: https://doi.org/10.1101/2020.08.11.246785

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