A balancing AKT: The E17K hotspot mutation and how it defines cancer
Compiling key proteins involved in key signaling pathways: EGF R, mTOR, NF-kB, and PI3K/AKT.
Learn about the conflicting nature of R-loops, a trending area of cancer research.Learn more
Fig. 1. Schematic drawing of the mTORC2 complex. mTORC2 contains mTOR, DEPTOR, mLST8, RICTOR, mSIN1, and PROTOR (Populo et al. 2012).
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase, which forms the core component of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (Bhat et al. 2015) (Figure 1). The complexes differ structurally and functionally, and have different sensitivity to the macrolide rapamycin.
mTORC1 regulates cell growth and proliferation by controlling protein synthesis, lipid synthesis, autophagy, and metabolic programs (Bhat et al. 2015 and Laplante and Sabatini 2012) and can be activated by various stimuli such as growth factors, nutrients, energy, and stress signals (Populo et al. 2012). The mTORC1 complex consists of mTOR, DEP domain-containing mTOR-interacting protein (DEPTOR), mammalian lethal with SEC13 protein 8 (mLST8), proline-rich AKT1 substrate 1 (PRAS40), and regulatory-associated protein of mTOR (RAPTOR) (Figure 2). mTOR is the catalytic subunit of the complex. DEPTOR binding to mTOR negatively regulates its kinase activity (Varusai and Nguyen 2018). mLST8 binding to the mTOR kinase domain stabilizes the RAPTOR-mTOR interaction (Kim et al. 2003). PRAS40 regulates mTORC1 kinase activity as a direct inhibitor of substrate binding (Wang et al. 2007). RAPTOR binding mediates mTOR’s function as a scaffold in the mTOR-signaling cascade and binds directly to mTOR (Hara et al. 2002).
One key role for mTOR is that of a negative regulator of autophagy (Mizushima et al. 2008). mTORC1 regulates this process by phosphorylation and suppression of the ULK-Atg13-FIP200 kinase complex, which is an essential mediator of autophagy. Inhibition of mTORC1 leads to autophagosome formation, which subsequently fuses with lysosomes (Jung et al. 2009; Laplante and Sabatini 2012). The death-associated protein 1 (DAP1) is also an mTOR substrate that negatively regulates autophagy (Koren et al. 2010).
Inhibition of mTORC1 kinase activity causes reduction in DAP1 phosphorylation, and converts the protein into an active suppressor of autophagy (Koren et al. 2010).
Information about the importance of the complex in the regulation of protein synthesis can be found on our translation factors page.
Fig. 2. The role of the mTORC1 complex in the regulation of autophagy. mTORC1 directly phosphorylates and inhibits the ULK-Atg13-FIP200 complex when nutrients are abundant. Phosphorylation of ULK1 and ATG13 prevents induction of autophagy. Upon starvation or rapamycin treatment, mTORC1 is inhibited, which enables the induction of autophagy (Jung et al 2009; Laplante and Sabatini 2012).
The mTORC2 complex regulates cell survival and cytoskeletal organization (Oh and Jacinto 2011) and can be activated by growth factor binding. The complex consists of mTOR, Deptor, mLST8, rapamycin-insensitive companion of mTOR (RICTOR), stress-activated protein kinase-interacting protein 1 (mSIN1), and protein observed with RICTOR (PROTOR) (Populo et al. 2012) (Figure 1). DEPTOR negatively regulates mTORC2 complex (Peterson et al. 2009). Knockout of mLST8 in mice reduces the activity of the complex (Guertin et al. 2006). RICTOR is a key component of the mTORC2 complex and interacts with PROTOR (Woo et al. 2007). It is overexpressed in various cancer types associated with poor survival outcomes (El Shamieh et al. 2018). The RICTOR and mTOR kinases both phosphorylate AKT at serine 473 (Hresko and Mueckler 2005; Sarbassov et al. 2005) as well as facilitate PDK1 mediated phosphorylation at AKT threonine residue 308 (Sarbassov et al. 2005). In addition, mSin1 has also been reported to play a role in mTORC2's capacity to phosphorylate AKT (Frias et al. 2006). PROTOR is a RICTOR-binding subunit of mTORC2 (Pearce at al. 2007) and is required for SGK1 activation in the kidney (Pearce et al. 2011).
Mutations in the mTOR signaling pathway as well as aberrant mTOR signaling have been associated with the development of many diseases including cancer (Populo et al. 2012). Therefore, mTOR represents an attractive therapeutic target (Bhat et al. 2015). Many mTOR inhibitors are licenced FDA-approved drugs and many more are currently being tested in clinical trials.
We have compiled key proteins involved in the mTOR signaling pathway into one handy poster you can download for your reference.
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