Carolina Franco Nitta, Department of Pathology, University of New Mexico, Albuquerque, United States
Ellen W. Green, Department of Pathology, University of New Mexico, Albuquerque, United States
Elton D. Jhamba, Department of Pathology, University of New Mexico, Albuquerque, United States
Justine M. Keth, Department of Pathology, University of New Mexico, Albuquerque, United States
Iraís Ortiz-Caraveo, Department of Pathology, University of New Mexico, Albuquerque, United States
Rachel M. Grattan, Department of Pathology, University of New Mexico, Albuquerque, United States
David J. Schodt, Department of Physics & Astronomy, University of New Mexico, Albuquerque, United States
Aubrey C. Gibson, Department of Pathology, University of New Mexico, Albuquerque, United States
Ashwani Rajput, Department of Surgery, University , Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of New Mexico, Albuquerque, United States,
Keith A. Lidke, Department of Physics & Astronomy, University of New Mexico, Albuquerque, United States,,Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
Bridget S. Wilson, Department of Pathology, University of New Mexico, Albuquerque, United States, , Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
Mara P. Steinkamp, Department of Pathology, University of New Mexico, Albuquerque, United States, ,Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
Diane S. Lidke, Department of Pathology, University of New Mexico, Albuquerque, United States, Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States

Document Type

Article

Publication Date

11-25-2021

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.

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