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- Title
EGFRAP encodes a new negative regulator of the EGFR acting in both normal and oncogenic EGFR/Ras-driven tissue morphogenesis.
- Authors
Soler Beatty, Jennifer; Molnar, Cristina; Luque, Carlos M.; de Celis, Jose F.; Martín-Bermudo, María D.
- Abstract
Activation of Ras signaling occurs in ~30% of human cancers. However, activated Ras alone is insufficient to produce malignancy. Thus, it is imperative to identify those genes cooperating with activated Ras in driving tumoral growth. In this work, we have identified a novel EGFR inhibitor, which we have named EGFRAP, for EGFR adaptor protein. Elimination of EGFRAP potentiates activated Ras-induced overgrowth in the Drosophila wing imaginal disc. We show that EGFRAP interacts physically with the phosphorylated form of EGFR via its SH2 domain. EGFRAP is expressed at high levels in regions of maximal EGFR/Ras pathway activity, such as at the presumptive wing margin. In addition, EGFRAP expression is up-regulated in conditions of oncogenic EGFR/Ras activation. Normal and oncogenic EGFR/Ras-mediated upregulation of EGRAP levels depend on the Notch pathway. We also find that elimination of EGFRAP does not affect overall organogenesis or viability. However, simultaneous downregulation of EGFRAP and its ortholog PVRAP results in defects associated with increased EGFR function. Based on these results, we propose that EGFRAP is a new negative regulator of the EGFR/Ras pathway, which, while being required redundantly for normal morphogenesis, behaves as an important modulator of EGFR/Ras-driven tissue hyperplasia. We suggest that the ability of EGFRAP to functionally inhibit the EGFR pathway in oncogenic cells results from the activation of a feedback loop leading to increase EGFRAP expression. This could act as a surveillance mechanism to prevent excessive EGFR activity and uncontrolled cell growth. Author summary: Activation of Ras signalling occurs in ~30% of human cancers. However, activated Ras alone is insufficient to produce malignancy. Thus, the discovery of genes cooperating with Ras in cancer is imperative to understand tumoral growth driven by Ras activating mutations. A key output of over-activated EGFR/Ras signalling is the induction of a complex and dynamic set of transcriptional networks leading to changes in gene expression. As a result of these changes, the normal function of some genes can become adjusted in a tumorigenic context. In this work, using the Drosophila wing imaginal disc as model system, we have identified a new EGFR inhibitor, EGFRAP, which function is redundant for proper morphogenesis, yet becomes an important limiter of the overgrowth driven by oncogenic EGFR/Ras activity. We show that the specificity of EGFRAP in cells with high levels of EGFR activity arises from activation of a negative feedback loop resulting in increased EGFRAP levels. This could act to prevent excessive EGFR activity and uncontrolled cell growth. We believe the identification of other factors behaving like EGFRAP, will help in our fight against cancer, as it might lead to the identification of new therapeutic drugs affecting cancer but not normal cells, a top priority in cancer research.
- Subjects
EPIDERMAL growth factor receptors; IMAGINAL disks; GENE regulatory networks; MORPHOGENESIS; ADAPTOR proteins; RAS oncogenes
- Publication
PLoS Genetics, 2021, Vol 17, Issue 8, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1009738