Question

While it is widely believed that the GTPase Rheb directly activates mTORC1, the ability of PA (18:1-16:0) to activate mTORC1 in the absence of Rheb strongly suggests that it is the ability of Rheb to activate PLD and generate PA is the last step in the activation mTORC1. True or false?

Answer 1

Solution

True.

GTPase Rheb could directly activate mTORC1 or through some other mediator such as PA (phosphatidic acid). But if Rheb were to be the terminal activator of mTORC1, Rheb when present alone with mTORC1 would activate it, without PA. But we can see that PA can activate mTORC1 without any other factors present, even Rheb. So, PA is the terminal activator of mTORC1.

This hVps34/Rheb-PLD1 pathway gives the outline required to understand the mTORC1 signalling. Amino acid mediates activation of hVps34 which in turn phosphorylates PI (phosphatidylinositol) to PI3P (phosphatidylinositol 3-phosphate). PIP3 interacts with the PX domain of PLD1 (phospholipase D1) and with the aid of Rheb activate it. PLD1 then generates PA from PC (phosphatidylcholine). PA then activates mTORC1.