scholarly journals Crystal structures of HER3 extracellular domain 4 in complex with the designed ankyrin-repeat protein D5

2021 ◽  
Vol 77 (7) ◽  
Author(s):  
Filip Radom ◽  
Clemens Vonrhein ◽  
Peer R. E. Mittl ◽  
Andreas Plückthun
Keyword(s):  
Growth Factor Receptor ◽  
Extracellular Domain ◽  
Ankyrin Repeat ◽  
Tumor Escape ◽  
Crystal Forms ◽  
Her Family ◽  
Epidermal Growth ◽  
Ankyrin Repeat Proteins ◽  
Selection Of ◽  
Domain 4

The members of the human epidermal growth factor receptor (HER) family are among the most intensely studied oncological targets. HER3 (ErbB3), which had long been neglected, has emerged as a key oncogene, regulating the activity of other receptors and being involved in progression and tumor escape in multiple types of cancer. Designed ankyrin-repeat proteins (DARPins) serve as antibody mimetics that have proven to be useful in the clinic, in diagnostics and in research. DARPins have previously been selected against EGFR (HER1), HER2 and HER4. In particular, their combination into bivalent binders that separate or lock receptors in their inactive conformation has proved to be a promising strategy for the design of potent anticancer therapeutics. Here, the selection of DARPins targeting extracellular domain 4 of HER3 (HER3d4) is described. One of the selected DARPins, D5, in complex with HER3d4 crystallized in two closely related crystal forms that diffracted to 2.3 and 2.0 Å resolution, respectively. The DARPin D5 epitope comprises HER3d4 residues 568–577. These residues also contribute to interactions within the tethered (inactive) and extended (active) conformations of the extracellular domain of HER3.

scholarly journals Designed ankyrin repeat proteins: a novel tool for testing epidermal growth factor receptor 2 expression in breast cancer

2010 ◽  
Vol 23 (9) ◽  
pp. 1289-1297 ◽  
Author(s):  
Jean-Philippe Theurillat ◽  
Birgit Dreier ◽  
Gabriela Nagy-Davidescu ◽  
Burkhardt Seifert ◽  
Silvia Behnke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Ankyrin Repeat ◽  
Repeat Proteins ◽  
Epidermal Growth ◽  
Ankyrin Repeat Proteins

scholarly journals A point mutation in the extracellular domain activates LET-23, the Caenorhabditis elegans epidermal growth factor receptor homolog.

1996 ◽  
Vol 16 (2) ◽  
pp. 529-537 ◽  
Author(s):  
W S Katz ◽  
G M Lesa ◽  
D Yannoukakos ◽  
T R Clandinin ◽  
J Schlessinger ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Caenorhabditis Elegans ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Point Mutation ◽  
Growth Factor Receptor ◽  
Extracellular Domain ◽  
Cysteine Residue ◽  
Loss Of Function ◽  
Epidermal Growth

The let-23 gene encodes a Caenorhabditis elegans homolog of the epidermal growth factor receptor (EGFR) necessary for vulval development. We have characterized a mutation of let-23 that activates the receptor and downstream signal transduction, leading to excess vulval differentiation. This mutation alters a conserved cysteine residue in the extracellular domain and is the first such point mutation in the EGFR subfamily of tyrosine kinases. Mutation of a different cysteine in the same subdomain causes a strong loss-of-function phenotype, suggesting that cysteines in this region are important for function and nonequivalent. Vulval precursor cells can generate either of two subsets of vulval cells (distinct fates) in response to sa62 activity. The fates produced depended on the copy number of the mutation, suggesting that quantitative differences in receptor activity influence the decision between these two fates.

scholarly journals Decorin Expression in Human Vulva Carcinoma: Oncosuppressive Effect of Decorin cDNA Transduction on Carcinoma Cells

2019 ◽  
Vol 67 (7) ◽  
pp. 511-522 ◽  
Author(s):  
Marie C. Nyman ◽  
Anne B. Jokilammi ◽  
Pia C. Boström ◽  
Samu H. Kurki ◽  
Annele O. Sainio ◽  
...  
Keyword(s):  
Cell Lines ◽  
Growth Factor Receptor ◽  
Tumor Stage ◽  
Carcinoma Cells ◽  
Tissue Samples ◽  
Her Family ◽  
Carcinoma Cell Lines ◽  
Epidermal Growth ◽  
Expression And Activity ◽  
Vulva Carcinoma

The extracellular matrix proteoglycan decorin is well-known for its oncosuppressive activity. Here, decorin expression was examined in human vulva carcinoma tissue samples and in primary and commercial cell lines representing this malignant disease. Furthermore, the effect of adenovirus-mediated decorin cDNA (Ad-DCN) transduction on the viability, proliferation, and the expression and activity of the epidermal growth factor receptor (ErbB/HER) family members of the cell lines were investigated. Using in situ hybridization and immunohistochemistry for decorin, it was demonstrated that malignant cells in human vulva carcinoma tissues lack decorin expression. This result was true independently on tumor stage, grade or human papillomavirus status. RT-qPCR analyses showed that the human vulva carcinoma cell lines used in this study were also negative for decorin expression. Transduction of the cell lines with Ad-DCN caused a marked reduction in cell viability, while the proliferation of the cells was not affected. Experiments examining potential mechanisms behind the oncosuppressive effect of Ad-DCN transduction revealed that ErbB2/HER2 expression and activity in carcinoma cells were markedly downregulated. In conclusion, the results of this study showed that human vulva carcinoma cells lack decorin expression, and that Ad-DCN transduction of these cells induces oncosuppressive activity in part via downregulation of ErbB2/HER2.

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