In this post, I am going to discuss my favorite pathway - the PI3-kinase/Akt and mTOR pathway. I personally like this pathway maybe because I have worked on it for almost two years and studied in-depth and realized how wonderful this pathway works.
In the previous post, we have seen that PIP2 is the source of diacylglycerol and IP3. Here, we will see that how PIP2 also serves as a starting point of another second messenger pathway. PIP2 is phosphorylated on another position 3 of inositol by an enzyme called as phosphatidylinositide 3-kinase (PI3-K). Just like phospholipase C, one form of PI3-K is activated by G-proteins while another form of PI3-K has SH2 domains which is activated by the association with protein tyrosine kinases. Phosphorylation of PIP2 yields the second messenger PIP3 phosphatidylinositol 3,4,5-triphosphate.
In the previous post, we have seen that PIP2 is the source of diacylglycerol and IP3. Here, we will see that how PIP2 also serves as a starting point of another second messenger pathway. PIP2 is phosphorylated on another position 3 of inositol by an enzyme called as phosphatidylinositide 3-kinase (PI3-K). Just like phospholipase C, one form of PI3-K is activated by G-proteins while another form of PI3-K has SH2 domains which is activated by the association with protein tyrosine kinases. Phosphorylation of PIP2 yields the second messenger PIP3 phosphatidylinositol 3,4,5-triphosphate.
Once, Akt is activated, it has a variety of target molecules which play an important role in cell differentiation, proliferation etc. These target molecules include protein kinases, transcription factors and various regulators of transcription. The important transcription factor that is the target of Akt is FOXO which belongs to the Forkhead family. Active (or phosphorylated) Akt phosphorylates FOXO. Once, FOXO is phosphorylated, it then creates a binding site for a cytosolic chaperone protein (14-3-3 protein) which then sequesters FOXO in inactive form in the cytoplasm (diagram on the left). Hence doesn't allow the FOXO to go into the nucleus and results in non-expression of FOXO-induced genes. When growth factors and Akt are not present, the FOXO is active and is released from 14-3-3-proteins and gets translocated to the nucleus. In the nucleus, it stimulates transcription of genes that inhibits cell proliferation of induces cell death.
Another target of Akt is another protein kinase GSK-3β. GSK-3β stands for glycogen synthase kinase-3β which is a serine/threonine kinase. It is involved actively in a number of pathways like proliferation, migration, inflammation etc. Just like the FOXO protein, the GSK-3β when phosphorylated is inhibited. Phosphorylation of GSK-3β generally inhibits the activity of its downstream target. So, what is the target of GSK-3β? The answer is - the translation initiation factor, eIF-2B. When this eIF-2B is phosphorylated by GSK-3β, it is inhibited and there is downregulation of overall translation initiation.
Now, this TSC1/2 is regulated by another protein kinase called AMPK, AMP-activated protein kinase. AMPK is the master metabolic switch and senses the energy state of the cell. That means when the levels of ATP inside the cell is low (AMP being high), AMPK gets activated. We can say that when the ratio AMP:ATP is high, AMPK is activated. This activated AMPK phosphorylates TSC1/2 thereby inhibiting mTOR/raptor pathway. Thus, when the energy levels of the cell are low, AMPK is activated which inhibits protein synthesis.
The active mTOR/raptor complex then further phosphorylates two very well known and well characterized targets as ribosomal protein, S6-kinase and eukaryotic initiation factor-4E (eIF4E) binding protein (4E-BP1). S6-kinase is a protein that controls translation by phosphorylating ribosomal protein S6 and some other proteins involved in translation. When mTOR is active, it phosphorylates S6-kinase which in turn phosphorylates ribosomal protein S6 and hence increases the rate of translation. Another protein 4E-BP1 controls translation by binding with eIF4E which binds to 5'cap of mRNA. When mTOR is active, 4E-BP is phosphorylated and this active 4E-BP prevents the binding to eIF-4E and leads to increased rates of translation whereas when mTOR is inactive, non-phosphorylated 4E-BPs bind to eIF4E and inhibits translation by interfering with the interaction of eIF4E and eIF4G.
No comments:
Post a Comment