PT  - JOURNAL ARTICLE
AU  - Carolina Franco Nitta
AU  - Ellen W. Green
AU  - Elton D. Jhamba
AU  - Justine M. Keth
AU  - Iraís Ortiz-Caraveo
AU  - Rachel M. Grattan
AU  - David J. Schodt
AU  - Aubrey C. Gibson
AU  - Ashwani Rajput
AU  - Keith A. Lidke
AU  - Mara P. Steinkamp
AU  - Bridget S. Wilson
AU  - Diane S. Lidke
TI  - EGFR transactivates RON to drive oncogenic crosstalk
AID  - 10.1101/2020.08.11.246785
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.11.246785
4099  - http://biorxiv.org/content/early/2020/08/12/2020.08.11.246785.short
4100  - http://biorxiv.org/content/early/2020/08/12/2020.08.11.246785.full
AB  - 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 StatementThe authors have declared no competing interest.