Below is a simplified schematic of the signaling cascade activated by the bindin

Question

Below is a simplified schematic of the signaling cascade activated by the binding of epidermal growth factor (EGF) to its membrane receptor on a target cell. This pathway involves a small G-protein called Ras. Ras is a G-protein similar to the ones that we’ve discussed in class. Activation of Ras involves the exchange of GDP for GTP and inactivation of Ras involves hydrolysis of GTP back to GDP by Ras’s intrinsic GTPase activity. The major steps involved in this pathway are described below.

1- EGF ligand binds to the EGF receptor

2-The ligand bound receptor becomes active through autophosphorylation and dimerization

3-Activation of the EGF receptor leads to the exchange of GDP for GTP and the activation of Ras.

4- Active Ras binds to and activates Raf kinase

5- Raf kinase phosphorylates and activates Mek kinase (Mek)

6- Mek kinase phosphorylates and activates ERK

7-Phorphorlyated ERK enters the nucleus and leads to the transcription of DNA and ultimately to cell proliferation.

Using the pathway described above, please answer the following questions.

A) Ras proteins are known to have mutations in the intrinsic GTPase activity leading to the inability to hydrolyze GTP to GDP. For a cell with this mutation, what would the effect be on cellular proliferation compared to a wild-type control cell that has been treated with EGF – increase, decrease, or no change? Explain your answer.

B) A deletion of the sequence that corresponds to the kinase domain of MEK will lead to a loss of kinase activity in MEK. For a cell with a mutated MEK protein (loss of kinase activity) what would the effect be on cellular proliferation compared to a wild-type control cell that has been treated with EGF – increase, decrease, or no change? Explain your answer

C) In certain types of cancer the EGFR receptor is known to be overexpressed in tumor cells. Based on the pathway discussed above, how does this overexpression lead to tumor growth.

Explanation / Answer

Ans- A ) as for activation of Ras , GTP is necessary, so in absence of GTP effect of EGF will be decreased. Ans-B ) all the intracellular proteins act in an cascade manner , inactivation of any of them would result in the decreased activity. Ans-C) as the ERK controls several transcription factors and also promotes. Cell proliferation hence increased activity of ERK system leads to tumor growth.

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