User:Tkadm30/Notebook/EGFR: Difference between revisions
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== EGF(R)-mediated drug delivery == | == EGF(R)-mediated drug delivery == | ||
* First please see this paper for background info on EGF(R) targeting [http://nrresource.org/Pathways/VDR%20Targets/92391.html here]. | * First please see this paper for background info on EGF(R) targeting [http://nrresource.org/Pathways/VDR%20Targets/92391.html 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 [http://openwetware.org/wiki/JHIBRG:Abstract_Apr_19_2007 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. | |||
__TOC__ | __TOC__ | ||
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* cytoplasm: outer edge of the cell membrane | * cytoplasm: outer edge of the cell membrane | ||
* oxidative phosphorylation: a enzymatic reaction converting energy from phosphate cleaving molecules to ATPase and NADPH substrates. | * oxidative phosphorylation: a enzymatic reaction converting energy from phosphate cleaving molecules to ATPase and NADPH substrates. | ||
* Fyn: A cell- | * Fyn: A cell-dependent tyrosine kinase ligand associated to the Fyn oncogene | ||
* Src: | * 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 === | === Case studies === | ||
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Selected readings: | Selected readings: | ||
* [http://jn.nutrition.org/content/137/3/548 (n-3) PUFA Alter Raft Lipid Composition and Decrease Epidermal Growth Factor Receptor Levels in Lipid Rafts of Human Breast Cancer Cells] | |||
* [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408375/ Epithelial Stem Cells: Turning over New Leaves] (Rockefeller University) | * [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408375/ Epithelial Stem Cells: Turning over New Leaves] (Rockefeller University) | ||
* [http://www.uniprot.org/uniprot/P06241 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 [http://chemwiki.ucdavis.edu/Organic_Chemistry/Virtual_Textbook_of_OChem/Amines/Nomenclature_and_Structure_of_Amines/Natural_Nitrogen_Compounds Natural Nitrogen Compounds] | |||
Notes: | Notes: | ||
* '''Receptor-associated''' tyrosine kinase signaling (SH2/SH3) for targeted drug delivery to epithelial stem cells membranes? | * '''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) ? | ** Calmodulin-dependent protein kinase receptors (Ca2+) signal transduction linked to Alzheimer like neuronal dysregulation? (ie: PH based phospholipid dysregulation) ? | ||
** [http://www.alzforum.org/new/detail.asp?id=1446 Endocannabinoids: Wet Blanket on Hippocampus Excitement] | ** [http://www.alzforum.org/new/detail.asp?id=1446 Endocannabinoids: Wet Blanket on Hippocampus Excitement]: What does this signify for [http://www.ncbi.nlm.nih.gov/pubmed/24120917 lipid rafts] based EGFR ligands ? | ||
*** '''Hippocampus''' dysregulation from calcium-dependent '''lipid-like''' signaling networks? | *** '''Hippocampus''' dysregulation from calcium-dependent '''lipid-like''' signaling networks? | ||
**** [[User:Etienne Robillard|Etienne Robillard]] 08:56, 4 May 2012 (EDT): 420 like (CB1 '''receptors''') to the rescue..? :) | **** [[User:Etienne Robillard|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 ? | **** 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 | ***** 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 ( | ***** 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? | ***** 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. | ***** 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. |
Latest revision as of 14:58, 2 October 2018
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.
- Hippocampus dysregulation from calcium-dependent lipid-like signaling networks?
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
-
C. Branden, J. Tooze, "Introduction to protein structure", [270-279]