4A. (3pts) One Please put an an \"I next of the following statements is generall

Question

4A. (3pts) One Please put an an "I next of the following statements is generally accurate, and the other one is not. next to the accurate statement and provide a supporting example. Please put o the inaccurate statement and provide a counter-examplo. GEF's activate signaling proteins, while GAP's inactivate them Supporting or counter-example: Kinases activate signaling proteins, while phosphatases inactivate them. B. (apts) Do you AGREE or DISAGREE with the following? Please provide your reasoning. The changes that kinases and Circle: phosphatases make to proteins are both energetically favorable. AGREE DISAGREE 5. In a biotech start-up, your goal is to develop & study drugs that can target RTK pathways that can lead to cancer. You decide to focus on the following pathway EGFR Grb2Sos RasRMek Erk Downstream response (cell proliferation) A. (2pts) Select one protein in this pathway. What molecular effect could your drug have on this protein to lead to increased cell division?

Explanation / Answer

4. (A) "A" GEF's activate signalling proteins while GAP's inactivate the.

A supporting example of the statement is the control of Ras-GTP and Ras-GDP bound states by GAP and GEF. The Ras-GDP bound state is exchanged for GTP by GEF ( Guanine nucleotide exchange factors- CDC25 and SOS) leading to activation and effecting downstream signalling cascades ( Rafs-, MEKK , etc. for cell differentiation and proliferation). On the contrary, The Ras-GTP bound state is inactivated b GAP or GTPase activating proteins ( neurofibromin) which activate the GTPase leading to release of Pi to form Ras-GDP bound state. In this way, the small GTPase family of Ras proteins are cycled into GTP and GDP bound forms by the action of GEF's and GAP's to effect signal transduction.

"I" Kinases activate signalling proteins while phosphatases inactivate them. The statement is inaccurate in some situation while accurate for other set of signalling proteins. Kinases and phosphatases and result in activate and inactivation of different signalling proteins. Both the proteins can either activate sepecific signalling proteins or inactivate them.  

For example: Phosphatases are required to inactivate signalling proteins that have been activated by phosphorylation. Tyrosine phosphatases such as SHP-1 and -2 have SH2 domains, and are recruited to the membrane following ligand-stimulated phosphorylation of receptors. SHP-1 binds to phosphotyrosines on activated cytokine receptors such as the erythropoietin (Epo) receptor, and is then phosphorylated by JAK2, which activates it. Active SHP-1 can downregulate (damp down) the JAK/STAT signalling pathway by dephosphorylating specific JAKs and STATs. It is therefore acting as a negative regulator of signalling proteins here.

However, Lck is a Src family tyrosine kinase is dephosphorylated and activated by the membrane-bound tyrosine phosphatase CD45. (role in activation of leukocytes following antigen presentation.) Therefore, in this case, the phosphatase acts as a positive regulator of signalling pathway where the phophorylated form of Lck is inactive ( inhibited) and release of the phosphate group results in activating it.

Therefore, kinases and phosphatase act positive and negative regulators ( or vice-versa) in signalling cascades.

(B) AGREE. The chages that kinases and phosphatases make to roteins are energetically favourable. THe overall phosphorylation reaction is reversible allowing the activity or inactivity of the enzyme/protein to be manipulated effectively in a controlled manner. Both phosphorylation and dephosphorylation result in a conformational change in the protein affecting its activity which can be reversibly changed without actually destroying the protein itself. The phosphorylation ( Kinases) and dephosphorylation ( phosphatases) , the overall phosphorylation reaction and the subsequent return to the original state of the protein is accompanied by AT hydrolysis ( or GTP hydrolysis) and hence it results in free-energy favourable changes.

5. (A). We select EGFR (Epidermal Growth factor Receptors) as a target for the drug. EGFR is a receptor tyrosine kinase which functions as a transmembrane ligand receptor ( epidermal growth factor, transforming growth gfactor - ligands). Acivation upon ligand binding leads to homodimerization ( monomer-inactive and dimer- active). Th homodimerization stimulates its intracellular protein kinase activity causing autophosphorylation and effecting downstream signalling via SH-2 binding domain phosphotyrosine kinsases ( downstream MAPK) playing role in cell proliferation.

To effect EFGR in a way such that it leads to decreased cell division, the drug which will be utilized should have a molecular effect of permanent binding to the EGFR ligand-binding site inhibiting its dimerization and autophosphorylation. Such a drug should be able to covalently bind to the EGFR making it constitutively inactive leading to inactivation of downstream signalling cascades to decrease cell proliferation and cell division. Therefore, the drug should be a tyrosine kinase inhibitor which should have the ability to permanently bind to the EGFR to result in its constitutive inactivation. Major drugs used for therapeutic effect in cancer treatment have the molecular property of targeting the EGFR.

For instance, Cetuximab (Erbitux) and Panitumumab (Vectibix) are two examples of monoclonal antibodies that are used to target the EGFR-ligand binding in the treatment of patients with metastatic colorectal cancer. Another such drug which targets EGFR activity is Lapatinib (Tykerb). It is a tyrosine kinase inhibitor which targets the ATP binding pocket of the kinase domain of EGFR and HER2. It binds to the intracellular phosphorylation domain to prevent receptor autophosphorylation upon ligand binding. It has therefore been used in treatment of HER2-positive breast cancer

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