Question

1. How does a PTB domain differ from and SH2 domain?

2. Which signaling pathway evokes most of the transformation phenotypes induced by the Ras oncoprotein?

3. Briefly explain how the AKT kinase gets recruited to the plasma membrane in response to PI3K signaling

4. How does the PTEN phosphatase negatively regulated AKT kinase?

Answer 1

1. A PTB domain is a phospho-tyrosine binding domain and a SH2 domain is Src homology region 2 domain. Both of these domains are present in many proteins and they are mainly involved in mediating protein-protein interactions. These domains are majorly present in tyrosine kinase receptors. Initially, it was identified that both of them identify phosphorylated tyrosine in receptor tyrosine kinases. But later it was seen that only SH2 domains bind to their targets strictly depending on tyrosine phosphorylation. While PTB domains can bind to their non-phosphorylated targets in a constitutive manner.

2. The RAF signalling pathway evokes most of the transformation phenotypes induced by the Ras oncoprotein. RAF is a very important effector molecule. The RAF then transduces the signal via MEK and ERK and finally leads to the synthesis of a large number of transcription factors that is responsible for the cell to proliferate. And proliferation is considered to be the major transformation phenotype of the RAS oncoprotein.

3. The signalling begins with the attachment of the ligand to the tyrosine kinase receptor. This leads to conformational changes in the receptor, dimerisation of the receptor and finally the phosphorylation of the tyrosine residue in the receptor domains. Following this activation, the receptor then recruits PI3K which then phosphorylates PIP2 to PIP3. Once PIP3 is formed, it recruits AKT to the plasma membrane and then the rest of the signal transduction continues.

4. PTEN is the main protein which is involved in the negative regulation of the PIK3-AKT pathway. This protein has a phosphatase activity and it converts PIP3 to PIP2. As a result AKT does not get recruited and the pathway gets inhibited.

The following diagram illustrates questions 3 and 4.