Abstract
The mammalian target of rapamycin (mTOR) is an evolutionary conserved Ser/Thr protein kinase that senses multiple upstream stimuli to control cell growth, metabolism, and autophagy. mTOR is the catalytic subunit of mTOR complex 1 (mTORC1). A significant amount of research has uncovered the signaling pathways regulated by mTORC1, and the involvement of these signaling cascades in human diseases like cancer, diabetes, and ageing. Here, we review advances in mTORC1 regulation by upstream stimuli. We specifically focus on how growth factors, amino acids, G-protein coupled receptors (GPCRs), phosphorylation, and small GTPases regulate mTORC1 activity and signaling.
Highlights
In 1964, a scientific expedition ventured to Rapa Nui to collect soil and plants samples [1,2,3]
Multiple upstream signals converge on tuberous sclerosis complex (TSC) to regulate mTOR complex 1 (mTORC1) activity
B1 (LKB1); mitogen-activated protein kinase (MAPK); MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK); protein 53 (p53); pleckstrin homology (PH); phosphoinositide-dependent kinase 1/2 (PDK1/2); phosphoinositide 3-kinase (PI3K); phosphatidylinositol 4,5-bisphosphate (PIP2 ); phosphatidylinositol 3,4,5-triphosphate (PIP3 ); phosphatase and tensin homolog (PTEN); rapidly accelerated fibrosarcoma (Raf); rat sarcoma (Ras); DNA damage response 1 (REDD1); Ras homolog enriched in brain (Rheb); p90 ribosomal S6 kinase (Rsk); son of sevenless homolog (SOS); tumor necrosis factor α (TNFα); tuberous sclerosis complex (TSC); wingless-type (Wnt)
Summary
In 1964, a scientific expedition ventured to Rapa Nui ( known as Easter Island) to collect soil and plants samples [1,2,3]. Mutations in the TOS motif were shown to render mTORC1 downstream targets, such as the phosphorylation of p70 ribosomal S6 kinase 1 (S6K1) and eIF4E-binding protein 1 (4EBP1, known as PHAS-1), insensitive to amino acid changes [22]. 95, discs large, zonula occludens-1 (PDZ) domain of DEPTOR directly interacts with mTOR to inhibit activity [26]. MTORC1 regulates a multitude of cellular processes, such as protein translation, autophagy, lysosome biogenesis, lipid synthesis, and growth factor signaling [38]. MTORC1 positively regulates SREBP through the phosphorylation and activation of S6K1 or through the multiple site phosphorylation and inhibition of Lipin, another mTORC1 substrate [43,44,45]. The postsynaptic density 95, discs large, zonula occludens-1 (PDZ) domain of DEPTOR directly interacts with mTOR to inhibit activity [26]. MTOR has been shown to promote its own activity via the E3 ubiquitin ligase Skp, Cullin, F-box (SCF) adaptor, βTrCP, mediated degradation of DEPTOR [28,29,30]
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