Based on this evidence, inhibiting mTOR signalling has gained great attention as anti-cancer therapy. Few mutations have been characterized in MTOR, the gene encoding for the mTOR kinase (Grabiner et al., 2014). Pathway hyperactivation occurs most commonly through loss-of-function mutations in tumor suppressors, such as phosphatase and tensin homolog (PTEN), tuberous sclerosis 1/2 (TSC1/2), neurofibromin 1/2 (NF1/2), as well as through oncogenic mutations in KRAS, PIK3CA, or AKT (Grabiner et al., 2014). Given its capability to integrate proliferative, antiapoptotic and angiogenic signalling by connecting VEGF, HIFs and growth factor receptors, the mTOR pathway has a pivotal role in human cancers. mTORC2 also regulates the organization of the actin cytoskeleton through activation of PKCα, paxillin and small GTPases, Rho and Rac (Laplante and Sabatini, 2012). mTORC2 is resistant to rapamycin: this complex may phosphorylate Akt at serine 473 (S473), required for Akt activation (Feldman et al., 2009). Protein observed with Rictor 1/2 (Protor 1/2) and DEPTOR are additional regulatory components (Li et al., 2014). The mTOR complex 2 (mTORC2) core is composed of mTOR, rapamycin insensitive companion of mTOR (Rictor), stress-activated protein kinase-interacting protein 1 (mSIN1) and mLST8. Moreover, mTOR regulates translation of the hypoxia inducible factor 1α (HIF-1α) and induces HIF-1/Vascular Endothelial Growth Factor (VEGF) dependent angiogenesis (Laughner et al., 2001). An important function of mTORC1 is the activation of ribosomal p70S6 kinase (S6K1) and suppression of 4E-BPs, resulting in enhanced translation of mRNAs encoding cell-cycle regulators and promotion of G1–S cell-cycle transition (Bjornsti and Houghton, 2004). mTORC1 is sensitive to the selective inhibitor rapamycin and is activated through growth factor via the canonical phosphoinositide 3-kinase (PI3K)/Akt pathway. Additional components include DEP-domain containing mTOR interacting protein (DEPTOR) and Proline–rich Akt substrate 40 kDa (PRAS40) (Li et al., 2014). ![]() The core components of mTOR complex 1 (mTORC1) consist of mTOR, mammalian lethal with sec-13 protein 8 (mLST8) and regulatory associated protein of TOR (Raptor). In mammalian cells, mTOR exists in two complexes, mTORC1 (Hara et al., 2002) and mTORC2 (Dos et al., 2004), which are differentially regulated and have distinct substrate specificities. ![]() The mammalian target of rapamycin (mTOR) is a serine/threonine-specific kinase able to regulate cell proliferation and survival by integrating nutrient, mitogenic and hormonal signals (Bjornsti and Houghton, 2004 Abraham and Gibbons, 2007).
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