title: Epidermal growth factor cytoplasmic domain affects ErbB protein degradation by the lysosomal and ubiquitin-proteasome pathway in human cancer cells.
abstract: The cytoplasmic domains of EGF-like ligands, including EGF cytoplasmic domain (EGFcyt), have important biological functions. Using specific constructs and peptides of human EGF cytoplasmic domain, we demonstrate that EGFcyt facilitates lysosomal and proteasomal protein degradation, and this coincided with growth inhibition of human thyroid and glioma carcinoma cells. EGFcyt and exon 22-23-encoded peptide (EGF22.23) enhanced procathepsin B (procathB) expression and procathB-mediated lysosomal degradation of EGFR/ErbB1 as determined by inhibitors for procathB and the lysosomal ATPase inhibitor BafA1. Presence of mbEGFctF, EGFcyt, EGF22.23, and exon 23-encoded peptides suppressed the expression of the deubiqitinating enzyme ubiquitin C-terminal hydrolase-L1 (UCH-L1). This coincided with hyperubiquitination of total cellular proteins and ErbB1/2 and reduced proteasome activity. Upon small interfering RNA-mediated silencing of endogenously expressed UCH-L1, a similar hyperubiquitinylation phenotype, reduced ErbB1/2 content, and attenuated growth was observed. The exon 23-encoded peptide region of EGFcyt was important for these biologic actions. Structural homology modeling of human EGFcyt showed that this molecular region formed an exposed surface loop. Peptides derived from this EGFcyt loop structure may aid in the design of novel peptide therapeutics aimed at inhibiting growth of cancer cells.
authors: Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors: Aleksandra
authors: A
authors: Glogowska
authors: Jörg
authors: J
authors: Stetefeld
authors: Ekkehard
authors: E
authors: Weber
authors: Saeid
authors: S
authors: Ghavami
authors: Cuong
authors: C
authors: Hoang-Vu
authors: Thomas
authors: T
authors: Klonisch
mesh_terms: D002401:Cathepsin B / Q000378:metabolism; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000737:chemistry* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005091:Exons; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D059748:Proteolysis; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002401:Cathepsin B; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D010455:Peptides; D046988:Proteasome Endopeptidase Complex; D018719:Erb-b2 Receptor Tyrosine Kinases; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; C507533:Ubiquitin carboxyl-Terminal Hydrolase L-1, human