mTORC1 and mTORC2 in cancer and the tumor microenvironment

Abstract

The mammalian target of rapamycin (mTOR) is a crucial signaling node that integrates environmental cues to regulate cell survival, proliferation and metabolism, and is often deregulated in human cancer. mTOR kinase acts in two functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), whose activities and substrate specificities are regulated by complex co-factors. Deregulation of this centralized signaling pathway has been associated with a variety of human diseases including diabetes, neurodegeneration and cancer. Although mTORC1 signaling has been extensively studied in cancer, recent discoveries indicate a subset of human cancers harboring amplifications in mTORC2-specific genes as the only actionable genomic alterations, suggesting a distinct role for mTORC2 in cancer as well. This review will summarize recent advances in dissecting the relative contributions of mTORC1 versus mTORC2 in cancer, their role in tumor-associated blood vessels and tumor immunity, and provide an update on mTOR inhibitors.

Figure 1. Schematic representation of mTOR complexes

mTORC1 consists of the mTOR kinase, mLST8, DEPTOR, Tti/Tel2, Raptor, and PRAS40. mTORC2 also shares the mTOR kinase, mLST8, Tti/Tel2, and DEPTOR, but contains unique components Rictor and mSin1. Rapamycin is a known allosteric inhibitor of mTORC1, while TOR kinase inhibitors (TOR-KIs) inhibit the activities of both complexes.

Figure 2. Overview of the mTOR signaling pathway

mTOR signaling is activated by a variety of environmental cues including growth factors, high cellular energy, and amino acids. Growth factors activate both mTORC1 and mTORC2, through binding of receptor tyrosine kinases (RTKs) or G-protein coupled receptors (GPCRs) and activation of PI3K or Ras-MAPK signaling cascades. PI3K phosphorylates PIP2 to increase the amount of PIP3 in the membrane, allowing co-localization of AKT, PDK1 and mTORC2. PDK1 phosphorylates AKT at T308, while mTORC2 phosphorylates AKT at S473 for complete activation. AKT in turn activates mTORC1 by inhibiting TSC2, a GAP for RHEB, an activator of mTORC1. AKT phosphorylation of PRAS40 promotes its dissociation from mTORC1 for full activation. ERK and RSK, both part of the Ras-MAPK signaling pathway, can also inhibit TSC2 to activate mTORC1 or activate mTORC1 directly through phosphorylation of PRAS40. High ATP levels in the cell inhibit AMPK, an activator of TSC2, thereby increasing the activities of RHEB and mTORC1. Intra-lysosomal arginine and cytoplasmic leucine stimulate Rag-dependent localization of mTORC1 to the lysosome where RHEB can activate mTORC1. Cytoplasmic glutamine triggers lysosomal localization of mTORC1 through a Rag-independent mechanism. Downstream targets of mTORC1 include S6K1 and 4EBP1, while downstream targets of mTORC2 include AKT, PKC, and SGK. S6K1 inhibits PI3K, completing a negative feedback loop on AKT signaling.