Structural Biochemistry/TOR

TOR is the target of rapamycin which is a macrolide used as an immunosuppressant for organ transplant. Its main function is to regulate cellular growth. It was originally found in yeast but the mammalian verision is mTORC. Dysregulation of TOR has been seen is several diseases such as cancer and diabetes. A lack of TOR mimics AA deprivation and starves cell of nutrients. TOR displays kinase activity towards proteins but not lipids. Two TOR complexes were found in yeast, TORC1 and TORC2.

mTORC1

The TORC1 form promotes cellular cellular growth and cell size by stimulating protein synthesis. TORC1 is activated by Amino acid signaling but also needs growth factors as stimuli. The mammalian form of TORC1, mTORC1, contains Raptor, mLST8 and PRAS40. TORC1 is able to react with the Deptor protein but seems to inhibit the activity of TORC1. Similar to Deptor, PRAS40 has the same effect of TORC1. Some of mTORC1 substrates include s6 kinase 4E-BP1 protein, Stat3 and potentially TSC, Ilk1 and Atg13. The phosphorylation of some of these substrates is not known.

mTORC2

mTORC2 contains Rictor, mDin1, mLST8, protor and is nutrient-insensitive. It can also react with Deptor but when it does it inhibits TORC1 activity. The substrates of mTORC2 have been implicated in cytoskeleton regulation and cell survival. Some substrates include Rictor and S6k but the best one is PKB/AKt which is key in the PI3K pathway. mTORC2 is needed to phosphorylate the turn motifs in PKB/Akt, SGK1 and protein kinase C. While phosphorylating PKB, mTorc2 also facilitates phosphorylation of Thr308. Phosphorylation of Thr308 is needed for PDK1 kinase activation. mTORC 2 is a target for drugs directed towards cancers that are defective in PTEN, a tumor suppressor. A downstream target of TORC2 is SGK1. Longterm rapamycin treatment should be used with caution because it may reduce mTORC2 functioning.

References

Information is from Joungmok Kim and Kun-Liang Guan