The activity of mTOR serine/threonine kinase, a critical regulator of cell growth and proliferation, is frequently deregulated in human cancer. Two canonical mTOR complexes, mTORC1 and mTORC2, each phosphorylate complex-specific substrates and are inhibited by Rapamycin. However, rapalogs proved to be mostly ineffective as cancer drugs in the clinic. Second-generation mTOR inhibitors suggested that rapalog resistance is caused by an unidentified Rapamycin insensitive mTOR activity. Researchers at St. Jude have discovered a novel mTOR complex, mTORC3, which embodies this activity. mTORC3 invariantly assembles in the cytoplasm upon expression of the ETS transcription factor ETV7. ETV7 directly binds mTOR creating a signaling complex with dual mTORC1/2 substrate specificity, but is devoid of mTORC1/2 components. mTORC3 activation occurs at high frequency in many types of human cancer and tumor cells become addicted to its proliferation and survival stimulatory effects. This discovery changes the mTOR paradigm and identifies a novel target for cancer drug development.
mTOR, sirolimus, Rapamycin, Torin1, PP242, KU63794, WYE35, Angiotensin II
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