TY - JOUR TI - EGFR transactivates RON to drive oncogenic crosstalk AU - Franco Nitta, Carolina AU - Green, Ellen W AU - Jhamba, Elton D AU - Keth, Justine M AU - Ortiz-Caraveo, Iraís AU - Grattan, Rachel M AU - Schodt, David J AU - Gibson, Aubrey C AU - Rajput, Ashwani AU - Lidke, Keith A AU - Wilson, Bridget S AU - Steinkamp, Mara P AU - Lidke, Diane S A2 - Mayor, Satyajit A2 - Cooper, Jonathan A VL - 10 PY - 2021 DA - 2021/11/25 SP - e63678 C1 - eLife 2021;10:e63678 DO - 10.7554/eLife.63678 UR - https://doi.org/10.7554/eLife.63678 AB - 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. KW - EGFR KW - RON KW - cell signaling KW - membrane biophysics KW - receptor tyrosine kinase JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -