Disease relevance of EGFR

• The EGFR cleavage fragment was detected in the membrane blebs in addition to the cell pellets [1].
• Epidermal growth factor (EGFR), oestrogen (ER), and progestin (PR) receptor concentrations were determined by radioligand binding assay in non-affected mammary tissues (n = 13) and benign (n = 11) and primary/locally recurrent malignant proliferative mammary lesions (n = 45) and metastases (n = 19) in 65 female dogs [2].
• We have previously shown that 47% of radiation-induced lung neoplasms in dogs exhibit increased expression of epidermal growth factor receptor (EGFR) [3].
• The transforming gene product of Fujinami sarcoma visue and EGF receptor kinase from A431 cells phosphorylated (Na+,K+)-ATPase poorly whereas casein was an excellent substrate [4].

High impact information on EGFR

• Disruption of GRB2 interactions by microinjection of a peptide corresponding to the GRB2 SH2 domain or its phosphopeptide ligand blocked EGF receptor endocytosis; other SH2 domains that bind EGF receptors or antibodies that neutralize RAS did not [5].
• Requirement for the adapter protein GRB2 in EGF receptor endocytosis [5].
• At the same time, the endosome gives rise to multivesicular endosomes (MVB) enriched in EGFR and to 60-nm-diam basolateral vesicles [6].
• At 20 degreesC dIgA-pIgR internalize to interconnected groups of vacuoles and tubules that comprise the endosomal compartment and in which they codistribute with internalized transferrin receptors (TR) and epidermal growth factor receptors (EGFR) [6].
• However, this pure endosomal signaling of EGFR does not stimulate cell proliferation, because EGFR only remained activated for less than 2 h following its stimulation at endosomes, while DNA synthesis generally requires growth factor exposure for 8 h or more [7].

Biological context of EGFR

• During this procedure we did not observe any surface EGFR phosphorylation [8].
• In this paper, we report the establishment of a system to specifically activate epidermal growth factor (EGF) receptor (EGFR) when it endocytoses into endosomes [8].
• We have demonstrated that 1 nm ouabain induced transactivation of the epidermal growth factor receptor (EGFR), resulting in increased proliferation and bromodeoxyuridine (BrdUrd) uptake [9].
• Epidermal growth factor receptor (EGFR) plays a critical role in cell proliferation, differentiation, and transformation [1].
• A cleavage-deficient EGFR mutant delayed apoptosis process [1].

Anatomical context of EGFR

• We propose that the differential sorting of occupied receptors within the MDCK endosome is achieved by this clathrin-based mechanism continuously retrieving receptors like TR from the pathways that deliver pIgR to the apical surface and EGFR to the lysosome [6].
• In the present study, using the well-established Madin-Darby canine kidney C7 cell line, we tested the hypothesis that EGFR represents a negative-feedback control for chronic aldosterone-induced Na(+) reabsorption [amiloride-inhibitable short-circuit current (I(sc))] [10].
• Together, these findings indicate that functional apical and basolateral EGFR exist on primary canine gastric epithelial cells and that these receptors regulate paracellular permeability [11].
• It was concluded that in the dog mammary gland EGFR expression is not associated with conditions of steroid receptor absence of biological agressiveness of neoplastic growth [2].
• In vascular smooth muscle cells the sodium pump complex can act as an intracellular signal transducing complex activated by low ouabain concentrations, which inhibit sufficient pumps to activate a transduction cascade via transactivation of EGFR, but insufficient pumps to alter intracellular ions [12].

Associations of EGFR with chemical compounds

• We also achieved specific activation of endosome-associated EGFR without using monensin [8].
• The endosome-associated EGFR was then activated by removing AG-1478 and monensin [8].
• Both ouabain-induced DNA synthesis (BrdUrd uptake) and MAPK42/44 phosphorylation were inhibited by the Src inhibitor PP2, the EGFR kinase inhibitor AG1478, the tyrosine kinase inhibitor genistein, and the MEK1 inhibitor PD98059 [9].
• Furthermore, aldosterone stimulated EGFR expression [10].
• Both apical and basolateral EGF activated tyrosine phosphorylation of EGF receptors (EGFR), beta-catenin, and cellular substrate as evident on confocal microscopy [11].

Physical interactions of EGFR

• Specific EGF receptor binding was determined in the presence of excess unlabeled EGF [13].

Other interactions of EGFR

• This treatment led to the internalization of nonactivated EGF-EGFR complexes into endosomes [8].
• An inverse correlation between EGFR and estrogen receptor (ER) was observed in 54% of the tumors [14].
• In this study, we investigated the expression of transforming growth factor alpha (TGF-alpha), a ligand for EGFR, to determine if an autocrine mechanism for growth stimulation was present in these tumors [3].

Analytical, diagnostic and therapeutic context of EGFR

• Immunoprecipitation and Western blotting showed that the EGFR and Src were phosphorylated within 5 min of 10(-9) m ouabain stimulation [9].
• Here, we tested the hypothesis that aldosterone uses the EGF-R as a heterologous signal transducer in MDCK cells [15].

References