module: dmel_egfr_signaling title: EGFR signaling pathway in Drosophila melanogaster label: EGFR signaling module_type: SIGNALING_PATHWAY description: >- Drosophila has a single EGF receptor (Egfr), a receptor tyrosine kinase activated by the TGF-alpha-like ligands Spitz, Keren and Gurken and the neuregulin-like ligand Vein. Spitz, Keren and Gurken are made as inactive membrane-bound precursors; the chaperone Star carries them from the endoplasmic reticulum to the Golgi, where rhomboid intramembrane proteases cleave them to release the secreted ligand. Ligand-bound Egfr recruits the adaptor Drk (Grb2) and the guanine nucleotide exchange factor Son of sevenless, which activates Ras85D. Ras triggers the Raf, Dsor1 (MEK) and Rolled (ERK) kinase cascade, assisted by the scaffolds KSR, CNK and Aveugle. ERK changes nuclear gene expression by activating the ETS factor Pointed and promoting the degradation or export of the repressors Yan (Aop) and Capicua. The pathway acts in oogenesis axis formation, photoreceptor recruitment, wing vein formation, and cell survival and proliferation in many tissues. summary: >- Rhomboid-processed EGF ligands activate Egfr, which signals through Drk, Sos, Ras and the Raf-Dsor1-Rolled cascade to control ETS and Capicua transcriptional outputs. concepts: - {id: GO:0007173, label: epidermal growth factor receptor signaling pathway} parts: - id: egfr_ligand_production label: EGFR ligand production role: ligand trafficking and processing description: >- Star escorts ligand precursors from the ER to the Golgi; the rhomboid proteases Rhomboid, Roughoid (Rhomboid-3), Stem cell tumor (Rhomboid-2) and Rhomboid-4 cleave them; Rasp N-palmitoylates Spitz. group: EGF-PRO complex: false unit_functions: rho: {id: GO:0004252, label: serine-type endopeptidase activity} ru: {id: GO:0004252, label: serine-type endopeptidase activity} stet: {id: GO:0004252, label: serine-type endopeptidase activity} - id: egfr_ligands label: EGFR ligands role: secreted ligands description: >- Spitz, Keren and Gurken are TGF-alpha-like ligands; Vein is a secreted neuregulin-like ligand that is not processed by rhomboids. genes: [spi, Krn, grk, vn] complex: false function: {id: GO:0008083, label: growth factor activity} - id: egfr_receptor label: Egfr role: receptor tyrosine kinase genes: [Egfr] complex: false function: {id: GO:0005006, label: epidermal growth factor receptor activity} - id: egfr_adaptors_and_ras_activation label: Receptor adaptors and Ras activation role: phosphotyrosine adaptors, phosphatase and exchange factors description: >- Drk and Shc bind the activated receptor; Corkscrew (SHP2) is a tyrosine phosphatase required for full Ras activation; Sos is the Ras exchange factor. Vav, a Rho-family exchange factor, is listed by FlyBase as both a core component and a negative regulator. genes: [drk, Shc, csw, Sos, Vav] complex: false unit_functions: csw: {id: GO:0004725, label: protein tyrosine phosphatase activity} Sos: {id: GO:0005085, label: guanyl-nucleotide exchange factor activity} - id: egfr_ras label: Ras85D role: small GTPase switch genes: [Ras85D] complex: false function: {id: GO:0003924, label: GTPase activity} - id: egfr_mapk_cascade label: Raf-Dsor1-Rolled MAP kinase cascade role: kinase cascade and scaffolds description: >- Raf (MAPKKK) phosphorylates Dsor1 (MEK), which phosphorylates Rolled (ERK). KSR, CNK and Aveugle are scaffolds that promote Raf activation. genes: [Raf, Dsor1, rl, ksr, cnk, ave] complex: false unit_functions: Raf: {id: GO:0004709, label: MAP kinase kinase kinase activity} Dsor1: {id: GO:0004708, label: MAP kinase kinase activity} rl: {id: GO:0004707, label: MAP kinase activity} - id: egfr_nuclear_output label: Nuclear transcriptional output role: transcription factors and co-repressor turnover description: >- Pointed is the ETS activator of target genes; Yan (Aop), Capicua (with the co-repressor Groucho) and Tramtrack are repressors that are relieved downstream of ERK. Phyllopod and Ebi act in signal-dependent turnover of repressors. Zpr1 is a FlyBase core component with less defined role. genes: [pnt, aop, cic, gro, ttk, phyl, ebi, Zpr1] complex: false unit_functions: pnt: {id: GO:0000981, label: "DNA-binding transcription factor activity, RNA polymerase II-specific"} aop: {id: GO:0001227, label: "DNA-binding transcription repressor activity, RNA polymerase II-specific"} cic: {id: GO:0001227, label: "DNA-binding transcription repressor activity, RNA polymerase II-specific"} ttk: {id: GO:0001227, label: "DNA-binding transcription repressor activity, RNA polymerase II-specific"} gro: {id: GO:0003714, label: transcription corepressor activity} connections: - {source: egfr_ligand_production, target: egfr_ligands, connection_type: PROVIDES_INPUT_FOR, description: "Star trafficking and rhomboid cleavage release active Spitz, Keren and Gurken."} - {source: egfr_ligands, target: egfr_receptor, connection_type: POSITIVELY_REGULATES, description: "Ligand binding induces Egfr dimerization and autophosphorylation."} - {source: egfr_receptor, target: egfr_adaptors_and_ras_activation, connection_type: POSITIVELY_REGULATES, description: "Phosphorylated Egfr recruits Drk/Shc and Sos."} - {source: egfr_adaptors_and_ras_activation, target: egfr_ras, connection_type: POSITIVELY_REGULATES, description: "Sos catalyses GDP-GTP exchange on Ras85D."} - {source: egfr_ras, target: egfr_mapk_cascade, connection_type: POSITIVELY_REGULATES, description: "GTP-bound Ras activates Raf."} - {source: egfr_mapk_cascade, target: egfr_nuclear_output, connection_type: POSITIVELY_REGULATES, description: "Rolled (ERK) phosphorylates Pointed, Yan and Capicua to change target gene transcription."} notes: >- Boundary. Core components (FlyBase EGFR-C) and ligand production (EGF-PRO). The Ras-MAPK cascade, adaptors and ETS outputs are shared with FGFR, Sevenless and Torso signaling. Feedback inhibitors (Argos, Sprouty, Kekkon1) and other FlyBase regulators are not parts. Protease activity is asserted only for the rhomboids whose ligand cleavage is well established (Rho, Roughoid, Stet).