Question 2-4. Cancer drugs and enzyme activity Many cancer drugs have been devel

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Question 2-4. Cancer drugs and enzyme activity Many cancer drugs have been developed that inhibit or activate enzyme function. a. Specific mutations in the EGFR and RAF have been shown to increase cancer risk. The EGFR is a receptor tyrosine kinase (RTK) and can become constitutively active in a cancer cell. Before we continue, explain how a RTK functions to transmit a signal (EGF) from the outside of the cel across the membrane to the inside of the cell. Be specific, what changes occur on the outside of the cell when ligand is bound? What changes occur on the inside of the cell that pass that information from the receptor to the first downstream target! I don't need the entire signal transduction cascade. Rubric (4): correct explanation with the effect of ligand binding by the receptor on outside of the cell (2) and effect of ligand binding on inside of the cell (2). Sorafenib is a tyrosine kinase inhibitor that affects RAF (kinase; a downstream target of the EGFR signal transduction cascade). The Kd for binding of Sorafenib to wild type RAF is 35 nmolL. The Kd for the binding of Sorafenib to an oncogenic mutation in RAF (V600E) is 14 nmol/L. Which form of BRAF does the drug bind to the best? Rubric (): To which form of the EGFR does ATP least tightly? b. Wild Type RAF, higher number less tightly bound c. Sorafenib drug binds to the ATP binding site of the oncogenic RAF kinase (V600E BRAF). What mechanism of inhibition do your think this drug employs on RAF kinase and why would it be most useful in cancers that carry the V600E mutation in RAF? Rubric (4): Type of inhibition is correct (2) and plausible explanation for drug's useful ness in cancer with V6oDE mutation (2). d. Researchers can assess the activity of RAF using kinase assays, but also by assessing whether downstream targets of the pathway have been activated. We know some of these proteins! In the experiment, cancer cells with constitutively active RAF are treated with or without Sorafenib (tyrosine kinase inhibitor). In these experiments, MEK was downregulated in the cells treated with Sorafenib when compared to untreated. Why does this make sense? Make sure you substantiate your answer with ?nepts ?vered this week Rubric (4) correct correlation is made between specific effect of the aug (1) and obvious applisatien of concepts taught Eis week is applied to the answer, and they are correct (3 765 words English (United States)

Explanation / Answer

a. The epidermal growth factor receptor (EGFR) is a transmembrane receptor protein embedded in the plasma membrane of many types of cells and is responsible for cell proliferation, movement, and carcinogenesis. Binding of the extracellular ligand, epidermal growth factor (EGF), activates EGFR by dimerisation of rtk.

in intracellular EGF induces prolonged tyrosine phosphorylation and partial activation of EGFR in an integrin-dependent and EGFR ligand-independent manner. Integrin-mediated activation of EGFR in epithelial cells is required for multiple signal transduction events previously shown to be induced by cell adhesion to matrix proteins, including tyrosine phosphorylation of Shc, Cbl, and phospholipase C?, and activation of the Ras/Erk and phosphatidylinositol 3?-kinase/Akt signaling pathways.

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