Signal rapamycin

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.

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). 

Brunn, G.J., Williams, J., Sabers, C., Weiderrecht, G., Lawrence, J. C., and Abraham, R. T. (1996). Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBOJ. 15, 5256-5267. 

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. 

Sirolimus (rapamycin) inhibits T-cell activation by inhibiting intracellular signal transmission by... 

A new class of immunosuppressive agents called proliferation-signal inhibitors (PSIs) includes sirolimus (rapamycin) and its derivative everolimus. The mechanism of action of PSIs differs from that of the calcineurin inhibitors. PSIs bind the circulating immunophilin FK506-binding protein 12, resulting in an active complex that blocks the molecular target of rapamycin (mTOR). 

Sehgal SN. 2006. Rapamune (RAPA, rapamycin, sirolimus) mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 39 484-489. 

Mechanism of Action. Unlike other immunosuppressants (cyclosporine, tacrolimus), sirolimus does not interfere directly with cytokine production. Instead, sirolimus inhibits the function of a specific enzyme commonly known as the mammalian target of rapamycin (mTOR).37,42 This enzyme plays a key role in signaling pathways that promote the growth and proliferation of T and B cells.37,45 By inhibiting this enzyme, sirolimus causes cell division to stop at a specific stage (Gl), thereby limiting the ability of these cells to mount an attack on transplanted tissues.65... 

Patterson C, Mapera S, Li HH, et al. Comparative effects of paclitaxel and rapamycin on smooth muscle migration and survival, Role of Akt-dependent signaling. Arterioscler Thromb Vase Biol 2006 26(7) 1479-1480. 

Chung J, Kuo CJ, Crabtree GR, Blenis J. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70kda S6 protein kinases. Cell 1992 69(7) 1227-1236. 

Marks AR, Rapamycin signaling in vascular smooth muscle. Transplant Proc 2003 35(suppl 3) 23 I S-233S. 

Oldham S, Hafen E. 2003. Insulin/IGF and target of rapamycin signaling a TOR de force in growth control. Trends Cell Biol 13 79-85. 

Bolster, D. R., Crozier, S. J., Kimball, S. R., and Jefferson, L. S. 2002. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 277 23977-23980. 

Sirolimus (rapamycin) is another macrolide, produced by Streptomyces hydroscopi-cus. Its immunosuppressant action, evidently, does not appear to involve inhibition of calcineurin. It forms a complex with the FK protein, imparting a special conformation on it and the complex then inhibits the mTOR (mammalian target of rapamycin) phosphatase. The latter operates in the signaling path leading from the interleukin-2 receptor to activation of mitosis in lymphocytes. Thus, sirolimus inhibits lymphocyte proliferation. It is approved for the prevention of transplant rejection. 

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