MTOR-pathway

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.

Lin F, Zhang PL, Yang XJ, Prichard JW, Lun M, Brown RE. (2006) Morphoproteomic and molecular concomitants of an overexpressed and activated mTOR pathway in renal cell carcinomas. Ann Clin Lab Sci 36 283-293. 

Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G Marciano R, Ciardiello F, Tortora G. (2008) Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer 98 923-930. 

Sirolimus binds to the cytosolic protein FK-binding protein R (FKBP-12) but does not block calcineurin activity. It does not bind to cyclophilins, which are cytosolic receptors for cyclosporine. Unlike cyclosporine and tacrolimus, sirolimus does not inhibit the activation of NFAT responsive genes. After binding to its cytosolic receptors, sirolimus inhibits a protein kinase, the mammalian target of rapamycin (mTOR) pathway, via suppression of PP2-A. When mTOR is inhibited, the cells will not proceed to the S phase, and the cell cycle will be blocked (Fig. 4.3). As a result, sirolimus blocks T-cell proliferation but its effects are downstream of the IL-2 receptors. IL-2 binding to its receptors activates intracellular protein kinases that in turn activate gene transcription and T-cell proliferation. 

Sarbassov Dos D, Ali SM, Sabatini DM. Growing roles for the mTOR pathway, Curr Opin Cell Biol 2005 17(6) 596—603. 

Takahashi, K., Nakagawa, M., Young, S.G., and Yamanaka, S. (2005). Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway. J Biol Chem 280 32768-32774. 

The phosphorylation of 4E-BP1 is under the control of at least two signaling pathways, the Akt-pathway and the mTOR-pathway, as discussed below. 

A further susceptible point for both the insulin-Akt signaling pathway and the mTOR pathway is the ribosomal protein S6. Under the influence of insulin, S6 is phosphorylated by a specific protein kinase, the p70S6 kinase (review Avruch et al., 2001), resulting in increased levels of translation of certain mRNAs. Several pathways, including the MAPK/ERK pathway (see Chapter 10) and the Akt kinase pathway, can contribute to the activation of the p70S6 kinase. 

Pantuck AJ, Seligson DB, Klatte T, et al. Prognostic televance of the mTOR pathway in tenal cell carcinoma implications for molecular patient selection fot tatgeted thetapy. Cancer. 2007 109 2257. 

Codeluppi S, Svensson Cl, Hefferan MP, Valencia F, Silldorff MD, Oshiro M, Marsala M, Pasquale EB (2009) The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord. J Neurosci 29 1093-1104... 

Inhibitors of Receptor Tyrosine Kinases and the PI3K/Akt/mTOR Pathway... 

PL3K and mTOR inhibitors. The antibiotic wortmannin-derivative PX-866 the mTOR pathway... 

Inhibitors of FAK. Verastem Inc (founded by Robert Weinberg) produces small molecular inhibitors of the FAK/PBK/Wnt/mTOR pathway VS-6063 (administered with paclitaxel) VS-4718 (to follow) www.verastem.com. 

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