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EGFR transactivates RON to drive oncogenic crosstalk
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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654365/ https://www.ncbi.nlm.nih.gov/pubmed/34821550 http://dx.doi.org/10.7554/eLife.63678 |
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author | Franco Nitta, Carolina Green, Ellen W Jhamba, Elton D Keth, Justine M Ortiz-Caraveo, Iraís Grattan, Rachel M Schodt, David J Gibson, Aubrey C Rajput, Ashwani Lidke, Keith A Wilson, Bridget S Steinkamp, Mara P Lidke, Diane S |
author_facet | Franco Nitta, Carolina Green, Ellen W Jhamba, Elton D Keth, Justine M Ortiz-Caraveo, Iraís Grattan, Rachel M Schodt, David J Gibson, Aubrey C Rajput, Ashwani Lidke, Keith A Wilson, Bridget S Steinkamp, Mara P Lidke, Diane S |
author_sort | Franco Nitta, Carolina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8654365 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-86543652021-12-09 EGFR transactivates RON to drive oncogenic crosstalk Franco Nitta, Carolina Green, Ellen W Jhamba, Elton D Keth, Justine M Ortiz-Caraveo, Iraís Grattan, Rachel M Schodt, David J Gibson, Aubrey C Rajput, Ashwani Lidke, Keith A Wilson, Bridget S Steinkamp, Mara P Lidke, Diane S eLife Cell Biology 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. eLife Sciences Publications, Ltd 2021-11-25 /pmc/articles/PMC8654365/ /pubmed/34821550 http://dx.doi.org/10.7554/eLife.63678 Text en © 2021, Franco Nitta et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Franco Nitta, Carolina Green, Ellen W Jhamba, Elton D Keth, Justine M Ortiz-Caraveo, Iraís Grattan, Rachel M Schodt, David J Gibson, Aubrey C Rajput, Ashwani Lidke, Keith A Wilson, Bridget S Steinkamp, Mara P Lidke, Diane S EGFR transactivates RON to drive oncogenic crosstalk |
title | EGFR transactivates RON to drive oncogenic crosstalk |
title_full | EGFR transactivates RON to drive oncogenic crosstalk |
title_fullStr | EGFR transactivates RON to drive oncogenic crosstalk |
title_full_unstemmed | EGFR transactivates RON to drive oncogenic crosstalk |
title_short | EGFR transactivates RON to drive oncogenic crosstalk |
title_sort | egfr transactivates ron to drive oncogenic crosstalk |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654365/ https://www.ncbi.nlm.nih.gov/pubmed/34821550 http://dx.doi.org/10.7554/eLife.63678 |
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