RRC ID 70846
Author Soler Beatty J, Molnar C, Luque CM, de Celis JF, Martín-Bermudo MD.
Title EGFRAP encodes a new negative regulator of the EGFR acting in both normal and oncogenic EGFR/Ras-driven tissue morphogenesis.
Journal PLoS Genet
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.
Volume 17(8)
Pages e1009738
Published 2021-8-1
DOI 10.1371/journal.pgen.1009738
PMID 34411095
PMC PMC8407591
MeSH Adaptor Proteins, Signal Transducing / genetics Animals Cell Cycle Cell Proliferation / genetics Drosophila Proteins / antagonists & inhibitors Drosophila Proteins / genetics Drosophila Proteins / metabolism Drosophila melanogaster / genetics ErbB Receptors / antagonists & inhibitors* ErbB Receptors / genetics ErbB Receptors / metabolism Gene Expression / genetics Gene Expression Regulation, Neoplastic / genetics Genes, ras / genetics* Genes, ras / physiology Imaginal Discs / metabolism Morphogenesis Phosphorylation Receptors, Invertebrate Peptide / antagonists & inhibitors Receptors, Invertebrate Peptide / genetics Receptors, Invertebrate Peptide / metabolism Signal Transduction / genetics ras Proteins / genetics
IF 5.175