Abstract
Multiple signalling events interact in cancer cells. Oncogenic Ras cooperates with Egfr, which cannot be explained by the canonical signalling paradigm. In turn, Egfr cooperates with Hedgehog signalling. How oncogenic Ras elicits and integrates Egfr and Hedgehog signals to drive overgrowth remains unclear. Using a Drosophila tumour model, we show that Egfr cooperates with oncogenic Ras via Arf6, which functions as a novel regulator of Hh signalling. Oncogenic Ras induces the expression of Egfr ligands. Egfr then signals through Arf6, which regulates Hh transport to promote Hh signalling. Blocking any step of this signalling cascade inhibits Hh signalling and correspondingly suppresses the growth of both, fly and human cancer cells harbouring oncogenic Ras mutations. These findings highlight a non-canonical Egfr signalling mechanism, centered on Arf6 as a novel regulator of Hh signalling. This explains both, the puzzling requirement of Egfr in oncogenic Ras-mediated overgrowth and the cooperation between Egfr and Hedgehog.
Highlights
Multiple signalling events interact in cancer cells
We investigated a role for Arf[6] in oncogenic Ras tumour overgrowth and found that Egfr promotes Arf[6] to interact with Hh
We over-expressed Egfr in wing discs and asked whether knocking down Arf[6] suppresses Egfr-mediated overgrowth effect and found that it does (Supplementary Fig. 2). These data support the notion that Egfr acts through Arf[6]
Summary
Multiple signalling events interact in cancer cells. Oncogenic Ras cooperates with Egfr, which cannot be explained by the canonical signalling paradigm. Blocking any step of this signalling cascade inhibits Hh signalling and correspondingly suppresses the growth of both, fly and human cancer cells harbouring oncogenic Ras mutations These findings highlight a non-canonical Egfr signalling mechanism, centered on Arf[6] as a novel regulator of Hh signalling. Consistent with this, blocking Egfr or Arf[6] suppresses Hh signalling and inhibits the growth of either fly or human cancer cells harbouring oncogenic Ras. Altogether, our data delineate a non-canonical Egfr signalling mechanism in which Arf[6] acts as a novel regulator of Hh signalling. Our data delineate a non-canonical Egfr signalling mechanism in which Arf[6] acts as a novel regulator of Hh signalling This explains the puzzling requirement of Egfr in oncogenic Ras-mediated overgrowth and the oncogenic cooperation between Egfr and Hh signalling
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
