20.11 : mTOR Signaling and Cancer Progression

All eukaryotic cells must regulate their growth depending on the cues from their environment.

Certain genes, such as the mechanistic target of rapamycin, or mTOR, respond to various factors to regulate fundamental cellular processes, including the availability of nutrients, growth factors, and cellular stress.

mTOR is a large protein kinase of mammalian cells that exists in two functionally distinct multiprotein complexes - mTOR complex 1 or mTORC1 and mTOR complex 2 or mTORC2.

Amongst an immensely complex mTOR signaling network, the PI(3)K/AKT/mTOR pathway plays a crucial role in cell growth control.

Upon stimulation by binding insulin or insulin-like growth factors, the receptor tyrosine kinases on the cell surface activate the downstream signaling molecule- phosphatidylinositol 3-kinase or PI(3)K.

Active PI(3)K generates phosphatidylinositol 3,4,5-trisphosphate or PIP3, which enables 3-phosphoinositide-dependent kinase 1 or PDK1 to phosphorylate and activate another protein called AKT.

Active AKT protein, in turn, phosphorylates and inhibits the activity of the growth-suppressing, tuberin-hamartin complex or TSC complex.

TSC complex has a GTPase-activating  activity. In its active state, it converts RHEB, a lysosomal membrane-bound  protein, from an active to inactive state, therefore keeping mTORC1 in its inactive state.

When AKT inactivates the TSC complex, RHEB  can remain in an active GTP-bound state. The active RHEB can further activate mTORC1.

Active mTORC1 supports cell growth and proliferation by upregulating biosynthesis of macromolecules, such as proteins and lipids, and downregulating autophagy.

Because of its key role in cell growth and metabolism, cancer cells often exploit the mTOR signaling pathway to facilitate the sustained growth of tumor cells. Therefore, the genes in the mTOR signaling pathways are commonly found to be mutated in human cancers.

Such mutations lead to abnormal activation of the mTOR pathway even in the absence of any appropriate signals.

As a result, cancer cells exploiting this pathway can evade autophagy and synthesize more proteins and lipids to support early tumor progression.