EGFR transactivates RON to drive oncogenic crosstalk

eLife

Rachel M Grattan¹  Elton D Jhamba¹  Ellen W Green¹  Iraís Ortiz-Caraveo¹  Aubrey C Gibson¹  Carolina Franco Nitta¹  Justine M Keth¹  Bridget S Wilson²  Diane S Lidke²  Mara P Steinkamp²  David J Schodt³  Keith A Lidke⁴  Ashwani Rajput⁵ 

[1] Department of Pathology, University of New Mexico, Albuquerque, United States;Department of Pathology, University of New Mexico, Albuquerque, United States;Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States;Department of Physics & Astronomy, University of New Mexico, Albuquerque, United States;Department of Physics & Astronomy, University of New Mexico, Albuquerque, United States;Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States;Department of Surgery, University of New Mexico, Albuquerque, United States;Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States;

关键词: EGFR;    RON;    cell signaling;    membrane biophysics;    receptor tyrosine kinase;    Human;   

DOI  :  10.7554/eLife.63678

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY