Animal models expand our understanding of oncogenic Ras signalling. How oncogenic Ras, Egfr and Hh signalling are integrated to concertedly drive tumour overgrowth remains unclear. Endocytosis and intracellular transport of the receptor–ligand complex modulate Hh signalling levels. Hh signalling is initiated by the interaction of Hh protein with its receptor Patched. On the other hand, Egfr has been shown to cooperate with Hedgehog (Hh) signalling, another oncogenic pathway, to drive basal cell carcinoma and melanomas. It is surprising that the action of an activated downstream oncogenic component still requires its upstream receptor. Docking proteins (such as the downstream of receptor kinases or drk) activate the guanine exchange factor Son of sevenless (Sos), which converts Ras from an inactive (GDP-bound) to an active (GTP-bound) state and leads to the MAPK signalling cascade and activation of downstream target molecules. EGFR ligands bind to and activate Egfr, which recruits docking proteins via its cytoplasmic domain. Paradoxically, oncogenic Ras cooperates with Egfr in cancers. The molecular mechanisms governing oncogenic Ras-driven cancers are complex and involve interacting signalling pathways. Activating mutations of the Ras gene are highly prevalent in human cancers and give rise to some of the most aggressive tumours. This explains both, the puzzling requirement of Egfr in oncogenic Ras-mediated overgrowth and the cooperation between Egfr and Hedgehog. These findings highlight a non-canonical Egfr signalling mechanism, centered on Arf6 as a novel regulator of 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. Egfr then signals through Arf6, which regulates Hh transport to promote Hh signalling. Oncogenic Ras induces the expression of Egfr ligands. Using a Drosophila tumour model, we show that Egfr cooperates with oncogenic Ras via Arf6, which functions as a novel regulator of Hh signalling. How oncogenic Ras elicits and integrates Egfr and Hedgehog signals to drive overgrowth remains unclear. In turn, Egfr cooperates with Hedgehog signalling.
Oncogenic Ras cooperates with Egfr, which cannot be explained by the canonical signalling paradigm. Multiple signalling events interact in cancer cells.
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