What is mTORC1 and mTORC2?
mTOR forms two multiprotein complexes, mTORC1 and mTORC2 which are composed of discrete protein binding partners to regulate cell growth, motility, and metabolism. These complexes are sensitive to distinct stimuli, as mTORC1 is sensitive to nutrients while mTORC2 is regulated via PI3K and growth factor signaling.
What does the mTOR pathway do?
The mTOR signaling pathway, which is often activated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell differentiation but also plays an important role in tumor metabolism.
What activates mTORC1?
Most specifically, carbohydrate consumption activates mTORC1 through the insulin growth factor pathway. In addition, amino acid consumption will stimulate mTORC1 through the branched chain amino acid/Rag pathway.
How does mTOR regulate autophagy?
mTORC1 tightly regulates autophagy by suppressing autophagy induction via phosphorylation-dependent inhibition of ULK1/2 and the VPS34 complex and by preventing global expression of lysosomal and autophagy genes through TFEB phosphorylation.
What is mTORC1 pathway?
Pathway Description: The first, mTOR complex 1 (mTORC1), is composed of mTOR, Raptor, GβL, and DEPTOR and is inhibited by rapamycin. It is a master growth regulator that senses and integrates diverse nutritional and environmental cues, including growth factors, energy levels, cellular stress, and amino acids.
What is rapamycin used for?
Rapamycin (Rapamune, Sirolimus) is a macrolide exhibiting potent antitumor and immunosuppressive activity [261,262]. Rapamycin is thus used in clinical settings to prevent rejection in organ transplantation and to treat certain types of cancer.
What is mTORC2?
mTOR Complex 2 (mTORC2) is an acutely rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling. The complex itself is rather large, consisting of seven protein subunits.
How does chloroquine inhibit autophagy?
Chloroquine (CQ), which is frequently used clinically as an antimalarial agent, is a classic inhibitor of autophagy that blocks the binding of autophagosomes to lysosomes by altering the acidic environment of lysosomes, resulting in the accumulation of a large number of degraded proteins in cells (8).
Does AMPK activate autophagy?
AMPK is one of the major autophagy regulators, and the role of AMPK in autophagy initiation has been clearly shown. Under glucose starvation, AMPK associates with and activates autophagy-initiating kinase Ulk1, which is an orthologue of yeast ATG1, the most upstream component of the autophagy machinery11,12,13.
Who discovered mTORC1?
In 1994, Stuart L. Schreiber, David M. Sabatini and Robert T. Abraham independently discovered a protein that directly interacts with FKBP12-rapamycin, which became known as mTOR due to its homology to the yeast TOR/DRR genes.
How does rapamycin inhibit mTORC1?
Rapamycin is the canonical inhibitor of the mTOR (mamma- lian target of rapamycin) serine/threonine kinase. In mammalian cells, rapamycin acts through an allosteric mechanism that acutely disables the nutrient-sensitive mTOR complex 1 (mTORC1), one of two large protein kinases that share mTOR as the catalytic subunit.
Is rapamycin an immunosuppressant?
Rapamycin has potent immunosuppressive properties reflecting its ability to disrupt cytokine signaling that promotes lymphocyte growth and differentiation. In IL-2-stimulated T cells, rapamycin impedes progression through the G1/S transition of the proliferation cycle, resulting in a mid-to-late G1 arrest.
What is the role of mTOR kinase in CRC?
We have previously shown that the mTOR kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis of CRC. However, the contribution of mTOR and its interaction partners toward regulating CRC progression and metastasis remains poorly understood.
What happens to RhoA and Rac1 in mTORC2 knockdown?
Furthermore, knockdown of mTORC1 and mTORC2 induced a mesenchymal–epithelial transition (MET) and enhanced chemosensitivity of CRCs to oxaliplatin. We observed increased cell–cell contact and decreased actin cytoskeletal remodeling concomitant with decreased activation of the small GTPases, RhoA and Rac1, upon inhibition of both mTORC1 and mTORC2.
Which is the drug that inhibits mTOR activity?
The bacterially derived drug rapamycin allosterically inhibits mTOR activity ( 10 ). mTORC1 is partially sensitive to rapamycin treatment, whereas mTORC2 is believed to be rapamycin-insensitive ( 10, 11 ).