Disease relevance of Egfr

• All ventral epidermal cells therefore require some level of EGFR signalling; high levels specify the denticle fate, while lower levels maintain smooth-cuticle cell survival [1].
• Overactivity of EGFR signaling, as achieved by heat-shock-driven activation of a wild-type rhomboid (rho) construct, or by loss of function of argos (aos) or yan, results in an hyperplasia and deformity of the head midline structures [2].
• These results on signaling between squamous and columnar epithelia are particularly significant in the context of in vitro studies using human cell lines that suggest a role for the Egfr/Ras pathway in metastasis and tumour progression [3].
• AarA, a Providencia stuartii RHO-related protein, is active in Drosophila on the fly EGFr ligands [4].
• This gene encodes a receptor tyrosine kinase related to the EGF-receptor, and its activation and overexpression are thought to play a critical part in melanoma formation [5].

Psychiatry related information on Egfr

• Activation of the EGFR/Ras pathway appears to promote proneural gene self-stimulation mediated by the SMC-specific enhancers [6].

High impact information on Egfr

• Antagonism between the EGF-receptor (EGFR) and Notch pathways in particular is well documented, although the underlying mechanism is poorly understood [7].
• EGFR signaling attenuates Groucho-dependent repression to antagonize Notch transcriptional output [7].
• A microRNA mediates EGF receptor signaling and promotes photoreceptor differentiation in the Drosophila eye [8].
• An EGFR/Ebi/Sno pathway promotes delta expression by inactivating Su(H)/SMRTER repression during inductive notch signaling [9].
• The membrane proteins Star and Rhomboid-1 have been genetically defined as the primary regulators of EGF receptor activation in Drosophila, but their molecular mechanisms have been elusive [10].

Biological context of Egfr

• The rate limiting component of Drosophila Egfr signaling is Rhomboid, a seven transmembrane domain protein, whose expression prefigures Egfr signaling [11].
• This mutant phenotype resembles the normal inductive function of Egfr in other developmental contexts, particularly during atonal-controlled neural recruitment of chordotonal sense organ precursors [12].
• During oogenesis, Top/Egfr activation is required for the establishment of the dorsal/ventral axis of the egg and the embryo [13].
• Egfr signaling regulates ommatidial rotation and cell motility in the Drosophila eye via MAPK/Pnt signaling and the Ras effector Canoe/AF6 [14].
• echinoid (ed) encodes an immunoglobulin domain-containing cell adhesion molecule that negatively regulates the Egfr signaling pathway during Drosophila photoreceptor development [15].

Anatomical context of Egfr

• These results suggest that inductive interactions between myotubes and their epidermal muscle attachment cells are initiated by the binding of Vein, to the Egfr on the surface of EMA cells [16].
• We show that the cell surface protein Echinoid is required to moderate Egfr signalling during R8 photoreceptor selection by the proneural gene atonal during Drosophila eye development [12].
• Grk is expressed in the oocyte and activates the Egfr in the surrounding follicle cells during oogenesis [17].
• After cleavage, the extracellular domain of Grk is secreted from the oocyte to activate the Egfr in the follicular epithelium [17].
• The result indicates that graded activation of the DER pathway may normally give rise to a repertoire of discrete cell fates in the ventral ectoderm [18].

Associations of Egfr with chemical compounds

• A further link between PC/PI content, endocytosis, and signaling is supported by genetic interactions of dCCT1 with Egfr, Notch, and genes affecting endosomal traffic [19].
• Addition of a secreted, but not the membrane-associated form of Spitz to S2 Drosophila cells expressing DER gives rise to a rapid tyrosine autophosphorylation of DER [18].
• The consequences of eliminating key D-raf regulatory domains and specific serine residues in the transmission of Egfr and lateral epidermal signals were also addressed here [20].
• Proneural Basic Helix-Loop-Helix Proteins and Epidermal Growth Factor Receptor Signaling Coordinately Regulate Cell Type Specification and cdk Inhibitor Expression during Development [21].
• EGFR is bound by several activating ligands including Transforming Growth Factor-alpha in vertebrates, and its homolog Spitz in Drosophila [22].

Physical interactions of Egfr

• However, it has not been determined whether Aos binds directly to DER or whether regulation of the DER activation occurs through some other mechanism [23].
• Finally, EGFR can be co-immunoprecipitated with anti-DE-cadherin and anti-Armadillo antibodies from embryonic protein extracts [24].
• The spitz gene is required for photoreceptor determination in the Drosophila eye where it interacts with the EGF receptor [25].
• Using the yeast two-hybrid system we show here, for the first time, that Gurken protein directly binds to the extracellular domain of Egfr [26].
• Mutations in Sos also interact with the Ellipse allele of the Drosophila EGF receptor [27].

Enzymatic interactions of Egfr

• The mammalian protein Eps15 is phosphorylated by EGF receptor tyrosine kinase and has been shown to interact with several components of the endocytic machinery [28].

Regulatory relationships of Egfr

• This work demonstrates that Spitz triggers the DER signaling cascade [18].
• Co-expression of ed and nrg in the eye exhibits a strong genetic synergy in inhibiting EGFR signaling [29].
• Patterned expression of the Drosophila rhomboid (rho) gene is thought to promote signaling by the EGF receptor (EGFR) in specific cell types [30].
• The transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis [31].
• rhomboid and Star interact synergistically to promote EGFR/MAPK signaling during Drosophila wing vein development [32].

Other interactions of Egfr

• Consistent with our loss-of-function studies, we demonstrate that ectopic overexpression of kek1 mimics a loss of EGFR activity [31].
• Gene dosage studies among ventrolateral genes suggest that the rho product (Rho) may facilitate Spi-EGF-R signaling, resulting in activation of RAS [33].
• The Drosophila rhomboid gene mediates the localized formation of wing veins and interacts genetically with components of the EGF-R signaling pathway [33].
• Here we show molecular and genetic evidence that Drosophila vein (vn) encodes a candidate EGFR ligand and that vn expression is spatially restricted [34].
• Furthermore, Aos can block the binding of secreted Spitz (sSpi), a transforming growth factor alpha-like ligand of DER, to the extracellular domain of DER [23].

Analytical, diagnostic and therapeutic context of Egfr

• To activate the pathway, we overexpressed an activated form of the EGFR (UAS-caEGFR), and an activated form of the signal transducer Raf (UAS-caRaf); we also over- or ectopically expressed the downstream homeobox transcription factor Mirror (UAS-mirr) and the ligand-activating serine protease Rhomboid (UAS-rho) [35].
• To elucidate the downstream events induced by this pathway, we used genome-wide cDNA microarray technology to identify potential EGFR targets in Drosophila oogenesis [35].
• A marginal association was seen with two polymorphic sites in Egfr; however, we failed to replicate these findings in a second population, or in a modified quantitative complementation test designed to specifically test the effects of the putative polymorphisms [36].
• The distribution of DER transcripts was analyzed by in situ hybridization [37].
• Genetic dissection of a neurodevelopmental pathway: Son of sevenless functions downstream of the sevenless and EGF receptor tyrosine kinases [27].

References