User:Tkadm30/Notebook/EGFR

EGF(R)-mediated drug delivery

• First please see this paper for background info on EGF(R) targeting here.
• Second, the aim of this wiki is to review the characterization of cancerogenic mutations occuring in multiple receptor-associated tyrosine kinase proteins targeting the EGF receptor and perhaps in cholesterol based lipid rafts including stearic acid (monosaturated) and fatty acids derived ligands expressing the Fyn gene.
• Further, the relationship between MAP kinase signaling cascades and EGFR-mediated over-expression is not fully understood.
• Thus it is not fully understood how small molecules aggregation (beta-amyloid) can modulate NMDA mediated neuronal distribution in the Hippocampus.

Glossary

• cytotoxic: toxicity factor to cells
• cytoplasm: outer edge of the cell membrane
• oxidative phosphorylation: a enzymatic reaction converting energy from phosphate cleaving molecules to ATPase and NADPH substrates.
• Fyn: A cell-dependent tyrosine kinase ligand associated to the Fyn oncogene
• Src: tyrosine kinase bound protein (GRB2/Ash) encoded by the c-Src gene divided in 3 receptor-associated domains (SH2, SH3, and PH).
• Tyrosine kinase: Tyrosine specific kinase (enzyme) member of the protein-coding kinases super family.

Case studies

Breast cancer epithelial stem cells switching and the risks of EGF(R)-targeted (Fyn/Src) phosphorylation

Selected readings:

• (n-3) PUFA Alter Raft Lipid Composition and Decrease Epidermal Growth Factor Receptor Levels in Lipid Rafts of Human Breast Cancer Cells
• Epithelial Stem Cells: Turning over New Leaves (Rockefeller University)
• Fyn (EC 2.7.10.2)
• Signal Transduction Cascades: http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/signals.htm#camp
• cAMP-dependent protein kinase type I-beta regulatory subunit: http://www.uniprot.org/uniprot/P31321
• cAMP-dependent protein kinase catalytic subunit alpha: http://www.uniprot.org/uniprot/P17612
• cAMP-dependent protein kinase type I-alpha regulatory subunit: http://www.uniprot.org/uniprot/P10644
  • OMIM.org Entry : http://www.omim.org/entry/188830 Gene found to be relevant for many site-directed cross-talk (mutagenesis) in the presence of elevated cAMP levels.
• Amyloid beta A4 protein: http://www.uniprot.org/uniprot/P05067

Chemopreventive role of bioflavonoids and endocannabinoids

Questions:

• endocannabinoids as metaplastic neuronal activitor ? (chemopreventive effect)
• in mitigating long-term oxidative species from EGFR targeted pathway? (lipid rafts?)
• What other ligases (ATPase/cAMP?) can be metabolized from long-term exposure to a DNA alkylating agent ?
• See also Natural Nitrogen Compounds

Notes:

• Receptor-associated tyrosine kinase signaling (SH2/SH3) for targeted drug delivery to epithelial stem cells membranes?
  • Calmodulin-dependent protein kinase receptors (Ca2+) signal transduction linked to Alzheimer like neuronal dysregulation? (ie: PH based phospholipid dysregulation) ?
  • Endocannabinoids: Wet Blanket on Hippocampus Excitement: What does this signify for lipid rafts based EGFR ligands ?
    • Hippocampus dysregulation from calcium-dependent lipid-like signaling networks?
      • Etienne Robillard 08:56, 4 May 2012 (EDT): 420 like (CB1 receptors) to the rescue..? :)
      • In other words, how can anandamide (endocannabinoids) be used as novel therapeutic to mediates neuronal dysregulation of the hippocampus and in particular breast cancer early cancerogenic mutations ?
        • Question: Is AChr dependent protein binding from endocannabinoid-specific activation (CB1-associated?):
        • Endocannabinoid-specific receptors preventing beta amyloid precursors (β-amyloid peptide (Aβ)) aggregating in lipid rafts from cell-protein (AChr) promoted binding site(s), thus autocleaving phospholipid residues from oxidative radicals ? (gp42 link?)
        • Question: How can tyrosine kinase derived substrates (from enzymatic reactions in C-domain (SH2) and N-domain (SH3)) can have a orthogonal role in Alzheimer pathogenesis and in targeted drug delivery?
        • Answer: As emerging hypothesis, phosphorylation-induced tyrosine kinase drug delivery and upregulation to epithelial stem cells may probably result in asymmetrical protein binding in cholesterol-based microdomains (lipid rafts) with ErbB specific ligands, thus triggering a signal transduction cascade from the activated Src/Fyn receptors.

TODO

• Is programmed cell-death from cell-specific DNA based gene regulation via p53 gene/protein is leading to cell apoptosis? If so, could DNA programmed apoptosis result from aggregated nanoparticles to epithelial/endothelial stem cells membranes (ie: immunoglobin-like domain receptor) ?
• Glycoproteins role in programmed cell division acting as a master toll-like switch for receptor-associated drug delivery? (ie: EGFR)
• On lipid rafts: "Plasma membranes are heterogeneous and contain microdomains for lipid composition and receptors, especially in T and B lymphocytes and mast cells. Rafts are a way of concentrating receptors, the lipids and lipid tethered proteins together to provide the elements needed to activate secondary signals." (http://bioweb.wku.edu/courses/biol566/L19SignalPathnonRPTK.html)
• Is the p53 gene dependent on genetical inheritance (DNA-protein interactions) to make epithelial stem cells vulnerable to cancerogenic mutations ?

Keywords

Src homology domains, SH2, SH3, PH (Pleckstrin Homology domain), cyclosporamide (a alkylating agent used in cancer therapy)

References

1. C. Branden, J. Tooze, "Introduction to protein structure", [270-279]