Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects.

摘要: Activation of PI3K/Akt/mTOR (mechanistic target rapamycin) signaling cascade has been shown in tumorigenesis numerous malignancies including glioblastoma (GB). This is frequently upregulated due to loss the tumor suppressor PTEN, a phosphatase that functions antagonistically PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 mTORC2, which are composed special binding partners. These complexes sensitive distinct stimuli. nutrients mTORC2 regulated via PI3K growth factor signaling. protein synthesis through downstream molecules: 4E-BP1 (also called EIF4E-BP1) S6K. Also, responsive phosphorylating C-terminal hydrophobic motif some AGC kinases like Akt SGK. plays crucial role maintenance normal cancer cells its association with ribosomes, involved cellular metabolic regulation. Both control each other as PRAS40 phosphorylation, disinhibits activity, while S6K Sin1 modulate activity. Another significant component Sin1, for complex formation function. Allosteric inhibitors mTOR, rapamycin rapalogs, have essentially ineffective clinical trials patients GB their incomplete inhibition or unexpected activation negative feedback loops. Novel ATP suppress activity completely total dephosphorylation substrate pS6KSer235/236, effectively suppressing demonstrated complete pAKTSer473. Furthermore, proliferation self-renewal stem targetable these novel inhibitors. Therefore, effectiveness can be estimated ability both 2 impede migration.