Signaling Protein and Cell Proliferation and Immune Response - Essay Example

?mTOR inhibitors The mammalian target of rapamycin (mTOR) is a eukaryotic signaling protein that regulates the cell growth, cell motility, cell survival and cell proliferation. It is also responsible for protein synthesis and transcription. mTOR belongs to the protein family of  phosphatidylinositol 3-kinase-related kinase. (Polunovsky and Houghton, 2010). mTOR plays an important role in the regulation of skeletal muscle hypertrophy. This protein was conserved from yeast to human. mTOR is an integrating protein as it receives inputs from the growth hormones, Insulin pathways and other energy expenditure sources. It integrates the cell signals that give information about the energy status of the cell, nutritional status, mitochondrial potential, oxygen tension, aminoacids, ATP, and growth signals. During nutritional deficiency, the mTOR signaling becomes active and increases the protein synthesis and increases the cell size. If something is lacking inside the cell, then mTOR will decrease the protein synthesis and thus decreases the cell size and there by reduces the energy expenditure of the cell and prevents cell proliferation. The mechanical induced overload-hypertropy is due to the mTOR and their activity is inhibited by the introduction of Rapamycin. (Polunovsky and Houghton, 2010). Immune system consists of many types of regulatory cells. The regulatory cells contribute to the immune tolerance and immune homeostasis through many different mechanisms. The manipulation of these cells therapeutically to improve the transplant tolerance has become the most important field of interest nowadays. The important subsets of T cells are the CD4 (helper T cells) and CD 8 (Cytotoxic T cells) cells. Of these two types, CD4 T cells are called as regulatory or suppressor T cells. These cells are responsible for the immune toleran ce. (Fernandez 2010). These cells instead of increasing the immune response, decreases it there by enabling the transplant to get adapted to the body. They play an important role in auto immune reaction. The balance between the regulatory and the effector T cells are much necessary for the immune response and also for the controlling of many diseases. The developments of these regulatory cells are mediated by the mammalian target of rapamycin signaling protein. (mTOR protein complex). Rapamycin is isolated from the soil bacterium Streptomyces hygroscopicus. Rapamycin is commonly used as the immune suppressive drug in the transplant recipients and also found to inhibit the intracellular kinase of mTOR. (Polunovsky and Houghton, 2010). mTOR the check point protein kinase was found to have a major effect on the cell proliferation and growth, it is also found to have many downstream targeting based on phosphorylation of the protein. The major inputs for this protein are obtained from the growth factors and growth hormones such as insulin, IGF-1 and IGF-2 and some extracellular amino acids. (Polunovsky and Houghton, 2010).mTOR can also identify the status of the energy requirements and the redox level of the cell. Considerable progress has been made in understanding the signaling network only after the identification of the mTOR protein kinase. If this pathway is dysregulated in the human system, it leads to certain diseases in the human, most importantly some cancers. So a detailed study about the protein is very important. mTORs are high molecular weight molecules with many conserved structural domains. They contain 2549 amino acids with N-terminal containing 20 tandem HEAT repeats. (Hay and Sonenberg 2004). mTOR contains two protein complexes mTORC1 and mTORC2. mTORC1 is the main upstream centre for growth factors, stress signals and nutrients. They also help to convert the anabolic and catabolic pathways of the cell for the normal functioning. The mTORC1 cell signaling is high associated with the human cancer. The signaling network of the mTOR contains many oncogenes such as EGFR, PDGFR, PI3K, Ras, Raf, S6K1, Akt and tumor suppressors such as PTEN, LKB1, PDCD4, NF1 and REDD1. (Polunovsky and Houghton, 2010). Mutation or hyper activation of these genes leads to sporadic human cancers. mTORC1 phosphorylates the S6K1 at the threonine T389 residue and this stimulates the subsequent phosphorylation in the PDK1 pathway. The active S6K1 then initiates the protein synthesis. mTOR C1 has the ability to inhibit some of the tumorogenic phenotypes and many clinical studies are being conducted to identify the treatment methods for cancer types. (Polunovsky and Houghton 2010). The blocking of the mTOR helps in promoting the progression of the differentiation of the T cells and inhibiting the Th cell populations. By regulating the Foxo controlling signal pathway, the mTOR are able to help in the recirculation of the T cells and they function to move the secondary lymphoid tissue. mTORC2 complex is an important regulator of cytoskeleton and stimulates the paxillin, RhoA, Rac1, protein kinase C alpha and CDC42. mTORC2 complex is composed of mTOR, Rapamycin- insensitive companion of mTOR ( Rictor), mammalian stress-active protein kinase interacting protein 1 ( mSIN1 ) and G –beta-L. (Polunovsky and Houghton, 2010).The downstream regulation of mTOR is through the transcription mechanism. Here the ribosomal bingind to the mRNA and the addition of the elongation factors to the ribosomes at the 40s subunit followed by the unwinding of the mRNA’s secondary structure directly or indirectly are the targets of mTOR. Fig 1: mTOR signaling pathway. Ref: http://www.genome.jp/kegg/pathway/hsa/hsa04150.html Fig 2: Primary structure of mTOR. Ref: http://genesdev.cshlp.org/content/18/16/1926/F1.expansion.html Fig 3: The mTOR activity regulated by the Growth factors mediated by the PI3K signaling pathway. The signaling pathway leads to the phosphorylation and inhibition of TSC2 by Akt and activation of Rheb subsequently the mTOR also. The mechanism of this is not known so far. Ref: http://genesdev.cshlp.org/content/18/16/1926/F3.expansion.html FOXP3: Forkhead Box P3 protein is a member of FOX protein family that is involved in the immune responses. FOXP3 are the major regulators of T cells in their development and function. FOXP3 are responsible for the transfer of the immune tolerance during graft transplantation. (Sauer et al. 2008). mTOR and Cell Tolerance: Rapaycin treatment has much importance in the T cell functioning and development. Studies have proved that Rapamycin binds to the T cell Receptor (TCR) and stimulates the T cells to generate anti inflammatory regulatory T cells. mTOR is a major component of the P13 K pathway. Studies show that P13 K pathway is a critical regulator of tolerance. The mTOR can integrate the environmental signals and thus it accepts the rapamycin. The use of rapamycin will inhibit the mTOR of the P13 K pathway and block the cell-cycle progression from the G1- S phase of the activated T cells. Rapamycin creates anergic T cells. This results in the induction of the tolerance. Rapamycin binds to the FK506-binding protein- 12 and forms a complex. This complex inhibits the function of the mTORC1, the protein whose activation is necessary for the protein synthesis and the cell cycle progression. The repeated stimulation of the murine T cells with Rapamycin for antigen specificity will produce CD4+ , CD 25+ cells. These cells had enhanced FOXP3 expression. (Jiang 2008). When a conditional mice without the Frap 1 gene (the gene that codes for mTOR ) was generated and observed. It was found that they produced T cells but they were not able to get differentiated into Th1 or Th2 or Th17 effector cells. It was also observed that the phosphorylation was very less in the downstream regulation of PKD1 signalling pathway. To great surprise they also found that the CD 4+ , CD 25+ and FOXp3+ regulatory cells were found at greater concentration than the wild-type T cells. Thus it was concluded that the mTOR regulates the differentiation of the Effector and the regulatory T cells. They are also found to play an important role in regulating the cytokine receptor signaling. Araki et al. (2009) study has shown that mTOR is the major regulator of memory CD8 T cell differentiation. On treating mice with rapamycin followed by the acute lymphocytic choriomeningitis virus (LCMV) infection and they monitored the level of the virus specific CD 8 cells responses. To their surprise they observed that rapamycin resulted in the increased level of virus specific CD8 T cells. Antigen specific CD 8 T cells were found in both the lymphoid and non-lymphoid organs. Thus they have concluded that rapamycin treatment can induce the immune tolerance level of the cells. The expansion and the contraction phase of the T cell were much effective because of the rapamycin treatment. The memory precursors were increased by rapamycin during expansion phase and the memory transition process was accelerated for the T cell differentiation program during the contraction phase. The Rapamycin was also found to regulate the FOXp3 expression in the regulatory T cells. Thus rapamycin was found to increase the tolerogenic environment. (Araki et al. 2009). Conclusion: mTOR is an important eukaryotic signaling protein. This protein is found to play an important role in cell proliferation and immune response. The over expression of this protein leads to many chronic diseases in human. The Immune tolerance was one of the major causes of the rapamycin. The rapamycin when binds to the mTOR complex, it stimulates the memory T cells to produce auto inflammatory T cells thus reducing the immunity in the cells and helping the cells in autoimmune reaction when a new organ is transplanted. Rapamycin mTOR inhibition was found to increase the immune tolerance and also increases the expression of the FOXp3 protein on the surface of the cells. The pharmacological action of inhibition of mTOR by rapamycin restores the suppressive action of the T cells. References: Araki, K., Turner, AP., Shaffer, VO., Gangappa, S., Keller, SA., Bachmann, MF., Larsen, CP., Ahmed, R 2009, “mTOR regulates memory CD8 T cell differentiation”, Nature, vol.460, no. 7251, 108–112 Fernandez, D 2010, “mTOR signaling: A central pathway to Pathogenesis in systemic lupus Erythematosus,” Discovery Medicine, vol. 9, no. 46, 173-178.. Hay, N and Sonenberg, N 2004, “Upstream and downstream of mTOR,” Genes & Development, vol.18, no.16, 1926–45. Jiang, S 2008, Regulatory T cells and Clinical application, Springer. Polunovsky, V and Houghton, PJ 2010, mTOR pathway and mTOR inhibitors in Cancer therapy, Springer Publications. Sauer, S., Bruno, L, Hertweck, A., Finlay, D., Leleu, M., Knight, ZA, Cantrell, D., Shokat, KM., Fisher, AG and Merkenschlager, M 2008, “T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR,” Proceedings of the National Academy of Sciences of the United States of America, vol.105, no.22, 7797– 7802. Read More