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Mammalian target of rapamycin (mTOR) is a component of the phosphatidylinositol 3‑kinase (PI3K) cell survival pathway which monitors the availability of nutrients, mitogenic signals and cellular energy and oxygen levels, and thus it is important in the regulation of cell growth and proliferation. Abnormal activation of the PI3K pathway is considered to be involved in many cancers, and increased activation of this pathway is often associated with resistance to cancer therapies. mTOR acts upstream and downstream of Akt, operating at a critical junction in the PI3K pathway.
mTOR can form two different multiprotein complexes, mTORC1 and mTORC2, which regulate the protein synthesis necessary for cell growth and proliferation. mTORC1 is partially inhibited by rapamycin; it unifies various signals that indicate the availability of growth factors, nutrients and energy in order to promote cellular growth and catabolic processes during stress. Active mTORC1 exerts numerous downstream biological effects, including the translation of mRNA by phosphorylating downstream targets, such as 4E‑BP1 and p70 S6 kinase, the suppression of autophagy through ULK1 and Atg13, ribosome biogenesis, and activation of transcription that results in increased mitochondrial activity or adipogenesis. mTORC2 promotes cell survival by activating Akt. mTORC2 regulates cytoskeletal dynamics, and ion transport and growth through activating PKCα and phosphorylating SGK1, respectively. mTOR is a downstream target of EGFR and MET signaling, and therefore is considered to be a therapeutically attractive target for the treatment of multiple types of cancer.
Figure 1. The signaling pathways upstream of mTORC1 and mTORC2.
Extensive researches have established a central role for mTOR in regulating a number of fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of diabetes and cancer, as well as the aging process. In addition, the evidence linking activated mTOR signaling to cancer has generated significant interest in targeting the pathway for cancer therapy and many rapamycin analogs (rapalogs) are now tested in clinic. In 2007, the Food and Drug Administration (FDA) approved the rapalog Temsirolimus for the treatment of advanced stage renal cell carcinoma, becoming the first mTOR inhibitor approved for cancer therapy. Recently, the rapalog Everolimus was approved for the treatment of Tuberous Sclerosis Complex, a relatively rare genetic disease caused by mutations in Tsc1/2, in which patients develop non-malignant tumors in a number of organs, including the brain. There are a number of clinical trials underway using rapalogs, which have shown promise in several malignancies that are often refractory to standard chemotherapies.
Although rapalogs and catalyticm TOR inhibitors have been successful in the context of immunosuppression and a small subset of cancer types, clear limitations have arisen that limit their utility. Specifically, given the important functions of mTOR in most human tissues, complete catalytic inhibition causes severe dose-limiting toxicities, while rapalogs also suffer from the drawbacks associated with lack of tissue specificity and unwanted disruption of mTORC2. Future work should focus on the development of mTOR-targeting therapeutics outside of these two modalities, such as truly mTORC1-specific inhibitors for use in neurodegeneration, diabetes, and life-span extension, or tissue-specific mTORC1 agonists for use in muscle wasting diseases and immunotherapy. Such methods will likely require going beyond targeting mTOR directly to instead developing compounds that modulate tissue-specific receptors or signaling molecules upstream of mTOR. Creative Biogene is able to offer various mTOR signaling pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.
mTOR Signaling Pathway Product Panel
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