MTor kinase

Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K., and Avruch, J. (2005). Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702-713. 

Everolimus (40 Afinitor ) Sirolimus (34) Macrolide antibiotic Semi-synthetic NP Microbial Anticancer Inhibits mTOR kinase activity 375-382... 

Extensive preclinical studies have shown that sensitivity to mTOR inhibition may correlate with aberrant activation of the PI3K pathway or loss of functional tuberous sclerosis complex (TSC), as occurred in patients with tuberous sclerosis syndrome [151,152]. Rapamycin (compound 31, Fig. 6), which was the first compound shown to inhibit mTOR kinase activity, is an approved drug for prevention of allograft rejection. Rapamycin is a macrocyclic... 

Skin A 73-year-old woman with metastatic renal cell carcinoma developed a pruritic rash after receiving two infusions of temsirolimus 25 mg/week the rash was located on both antecubital areas and the backs of the knees [105 ]. Biopsy showed spongiotic dermatitis with eosinophils. The authors hypothesized that temsirolimus, an mTOR kinase inhibitor, has a direct inhibitory effect on signalling pathways that regulate cell growth and tissue repair. 

Wyeth (2009) 3-Substituted-lH-indole compounds, their use as MTOR kinase and PI3 kinase inhibitors, and their synthesis. Patent US2009/311217 (Al)... 

Sirolimus (SRL), also termed rapamycin is a macrolide lactone isolated from the ascomycete species Stre-ptomyces hygroscopicus. After binding to its cytosolic receptor FKBP-12 the resulting complex inhibits the multifunctional serine-threonine kinase mTOR (mammalian target of rapamycin). Inhibition of mTOR prevents activation of the p70S6 kinase and successive... 

Rapamycin is an immunosuppressive diug and an inhibitor of S6K1 (also known as p70S6-kinase) which phosphorylates ribosomal S6 protein. S6K1 is activated in response to insulin via activation of Akt. Rapamycin binds to a specific target protein (mTOR, mammalian target of rapamycin) which is functionally located downstream of Akt, but upstream... 

TOR Signalling. Figure 2 Dimeric structure of mTORCI and mTORC2. mTORCI contains mTOR, raptor and mLST8. Raptor binds the HEAT repeats of mTOR, mLST8 binds the kinase domain of mTOR. mTORC2 contains mTOR, rictor, Sini and mLST8. Rictor and Sini cooperatively bind the HEAT repeats of mTOR. 

Insulin and other growth factors result in the phosphorylation of BP-1 at five unique sites. Phosphorylation of BP-1 results in its dissociation from 4E, and it cannot rebind until critical sites are dephosphorylated. The protein kinase responsible has not been identified, but it appears to be different from the one that phos-phorylates 4E. A kinase in the mammalian target of rapamycin (mTOR) pathway, perhaps mTOR itself, is involved. These effects on the activation of 4E explain in part how insuhn causes a marked posttranscriptional... 

Figure 38-7. Activation of elF-4E by insulin and formation of the cap binding elF-4F complex. The 4F-cap mRNA complex is depicted as in Figure 38-6. The 4F complex consists of elF-4E (4E), elF-4A, and elF-4G. 4E is inactive when bound by one ofa family of binding proteins (4E-BPs). Insulin and mitogenic factors (eg, IGF-1, PDGF, interleukin-2, and angiotensin II) activate a serine protein kinase in the mTOR pathway, and this results in the phosphorylation of 4E-BP. Phosphorylated 4E-BP dissociates from 4E, and the latter is then able to form the 4F complex and bind to the mRNA cap. These growth peptides also phosphorylate 4E itself by activating a component of the MAP kinase pathway. Phosphorylated 4E binds much more avidly to the cap than does nonphosphorylated 4E.

Figure 7.1 Major signaling pathways relevant to this chapter. Simplified schematic diagram of the major signaling pathways which impinge on mRNA translation I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway II/III. MAP kinases, especially the classical MAP kinase (ERK) pathway and the p38 MAP kinase pathway IV. The mammalian target of rapamycin (mTOR) pathway. Strictly, this diagram shows the rapamycin-sensitive events linked to mTORCl. Selected inhibitors and their sites of action are shown. A numberof components and cross-connections have been omitted for clarity.

Wortmannin PI 3-kinase (Arcaro and Wymann, 1993) May also inhibit mTOR (Brunn et al., 1996)... 

Rapamycin is widely used as an inhibitor of mTORCl and does indeed very effectively block a number of events downstream of mT OR, for example, the activation of the S6 kinases and the phosphorylation of S6. As mentioned, signaling downstream of mTORC2 is not sensitive to rapamycin, at least in the short term (a few hours), although in the long term, it may be affected (Sarbassov et al, 2006). In addition, rapamycin does not inhibit all the effects attributed to mTORCl, such as, the phosphorylation of the N-terminal sites in 4E-BP1 (Thr37/46 in human cells see later for further discussion). As noted already, inhibitors of PI 3-kinase, especially LY294002, also inhibit mTOR (Brunn et al., 1996). 

Holz, M. K., and Blenis, J. (2005). Identification of S6 kinase 1 as a novel mammalian target ofrapamycin (mTOR)-phosphorylating kinase. J. Biol. Chem. 280, 26089-26093. 

Manning, B. D., and Cantley, L. C. (2003). United at last The tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signaling. Biochem. Soc. Trans. 31, 573-578. 

Cao, P. Maira, SM., Garcia-Echeverria, C. and Hedley, DW. (2009) Br. J. Cancer, Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xengrafts. 100, 1267-1276. 

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