The juxtamembrane regions of the epidermal growth factor receptor and gp185erbB-2 determine the specificity of signal transduction

1991 ◽  
Vol 11 (6) ◽  
pp. 3191-3202
Author(s):  
O Segatto ◽  
F Lonardo ◽  
D Wexler ◽  
F Fazioli ◽  
J H Pierce ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Mutational Analysis ◽  
Growth Factor Receptor ◽  
Tyrosine Kinase Domain ◽  
Amino Terminal ◽  
Epidermal Growth

The epidermal growth factor receptor (EGFR) and gp185erbB-2 are closely related tyrosine kinases. Despite extensive sequence and structural homology, these two receptors display quantitative and qualitative differences in their ability to couple with mitogenic signalling pathways. By using chimeric molecules between EGFR and erbB-2, we found that the determinants responsible for the specificity of mitogenic signal transduction are located in the amino-terminal half of the tyrosine kinase domain of either receptor. In the EGFR, mutational analysis within this subdomain revealed that deletion of residues 660 to 667 impaired receptor mitogenic activity without affecting its tyrosine kinase properties. This sequence is therefore likely to contribute to the specificity of substrate recognition by the EGFR kinase.

scholarly journals The juxtamembrane regions of the epidermal growth factor receptor and gp185erbB-2 determine the specificity of signal transduction.

1991 ◽  
Vol 11 (6) ◽  
pp. 3191-3202 ◽  
Author(s):  
O Segatto ◽  
F Lonardo ◽  
D Wexler ◽  
F Fazioli ◽  
J H Pierce ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Mutational Analysis ◽  
Growth Factor Receptor ◽  
Tyrosine Kinase Domain ◽  
Amino Terminal ◽  
Epidermal Growth

The epidermal growth factor receptor (EGFR) and gp185erbB-2 are closely related tyrosine kinases. Despite extensive sequence and structural homology, these two receptors display quantitative and qualitative differences in their ability to couple with mitogenic signalling pathways. By using chimeric molecules between EGFR and erbB-2, we found that the determinants responsible for the specificity of mitogenic signal transduction are located in the amino-terminal half of the tyrosine kinase domain of either receptor. In the EGFR, mutational analysis within this subdomain revealed that deletion of residues 660 to 667 impaired receptor mitogenic activity without affecting its tyrosine kinase properties. This sequence is therefore likely to contribute to the specificity of substrate recognition by the EGFR kinase.

scholarly journals Trastuzumab Blocks the Receiver Function of HER2 Leading to the Population Shifts of HER2-Containing Homodimers and Heterodimers

Antibodies ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 7
Author(s):  
Jun Zhao ◽  
Nishant Mohan ◽  
Ruth Nussinov ◽  
Buyong Ma ◽  
Wen Jin Wu
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Tyrosine Kinase Domain ◽  
Her Family ◽  
Human Epidermal Growth Factor ◽  
Epidermal Growth

HER2, a member of the Erythroblastosis Protein B/Human Epidermal Growth Factor Receptor (ErbB/HER) family of receptor tyrosine kinase, is overexpressed in 20~30% of human breast cancers. Trastuzumab, a HER2-targeted therapeutic monoclonal antibody, was developed to interfere with the homodimerization of HER2 in HER2-overexpressing breast cancer cells, which attenuates HER2-mediated signaling. Trastuzumab binds to the domain IV of the HER2 extracellular domain and does not directly block the dimerization interface of HER2-HER2 molecules. The three-dimensional structures of the tyrosine kinase domains of ErbB/HER family receptors show asymmetrical packing of the two monomers with distinct conformations. One monomer functions as an activator, whereas the other acts as a receiver. Once activated, the receiver monomer phosphorylates the activator or other proteins. Interestingly, in our previous work, we found that the binding of trastuzumab induced phosphorylation of HER2 with the phosphorylation pattern of HER2 that is different from that mediated by epidermal growth factor (EGF) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Binding of trastuzumab to HER2 promoted an allosteric effect of HER2, in both tyrosine kinase domain and ectodomain of HER2 although details of allosteric regulation were missing. In this study, we utilized molecular dynamics (MD) simulations to model the allosteric consequences of trastuzumab binding to HER2 homodimers and heterodimers, along with the apo forms as controls. We focused on the conformational changes of HER2 in its monomeric and dimeric forms. The data indicated the apparent dual role of trastuzumab as an antagonist and an agonist. The molecular details of the simulation provide an atomic level description and molecular insight into the action of HER2-targeted antibody therapeutics.

scholarly journals Use of Marine biotoxins to modulate the tyrosine kinase domain of the human epidermal growth factor receptor

2021 ◽  
Author(s):  
Charli Deepak Arulanandam ◽  
Ramesh Dharmara ◽  
Prathiviraj Ragothaman ◽  
Samuel Gnana Prakash Vincent
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Molecular Docking ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Marine Biotoxins ◽  
Epidermal Growth

Inappropriate activation of the Epidermal growth factor receptor (EGFR) group of kinases has been identified in a variety of tumour cells, either due to mutation or overexpression. Although the tumour is a fatal disease, significant therapy discoveries have lately been made. The human EGFR and this family of kinases have emerged as promising targets for cancer therapy. In this molecular docking study, Natural marine toxins are employed to regulate the activity of the human EGFR tyrosine kinase domain (EGFRtkd) in the molecular docking investigation (PDB ID5JEB). Marine biotoxins can cause neurological, gastrointestinal, and cardiovascular problems, as well as severe mortality and long-term morbidity in some situations. Because there is no antidote for any of the natural marine poisons, supportive care is the mainstay of treatment. Paralytic shellfish poisoning, in particular, and puffer fish poisoning, in particular, can result in death within hours of exposure to the poisons and may require immediate medical intervention. However, this research found that marine biotoxins can modulate EGFRtkd. Furthermore, homoyessotoxin was anticipated to be an EGFRtkd modulator with a binding affinity as -9.584 kcal/mol. To employ the homoyessotoxin in tumour therapies, further knowledge of natural marine biotoxins and further toxicological research is required.

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