Wednesday, 17 April 2013

A novel protein, UCH-L1, regulates the balance of two mTOR protein complexes; potential implications for neurological diseases and cancer

The signaling protein mTOR was first identified as the target of a natural chemical called Rapamycin and so named mammalian Target Of Rapamycin. mTOR can form two distinct complexes called mTORC1 and mTORC2; the two main mTOR binding proteins in these complexes are Raptor (mTORC1) and Rictor (mTORC2). In addition, several other proteins have been shown to associate with these complexes, for a review see this paper.


The mTORC1 complex activates S6K-1 and elF4E, two proteins required for the process of translating the messenger RNA of a gene into the protein via the assembly of amino acids specifically recruited by transfer RNA (tRNA). Increased mTORC1 activity can therefore lead to increased protein synthesis, important for bringing about dramatic cellular changes such as transformation from normal to cancerous states.


The mTORC2 complex, on the other hand, is responsible for activating proteins including: Akt, SGK-1 and PKCalpha which are involved in overall activation and proliferation of cells including those of the immune system. Cancerous cells often show increased Akt activation and this can be either through enhancing mutations in Akt itself or increased activity of Akt activating signaling pathways such as the mTOR pathway.
Since the discovery of Rapamycin, there have been a plethora of drugs developed which target either both mTOCR1, mTORC2 or both complexes. Some of these drugs have even been approved for the treatment of cancer, or are currently progressing through the later stages of clinical trials. However, the processes regulating the shift between mTORC1 and mTORC2 signaling are relatively poorly understood. A recent study by a group from Minnesota in the USA reveals a mechanism by which cells can move mTOR signaling from protein synthesis (mTORC1) to proliferation (mTORC2).

The ubiquitin hydrolase, UCH-L1, was the focus of a recent study as it was found that this protein interrupts mTORC1 signaling, high levels of UCH-L1 were associated with low levels of mTORC1 activity. UCH-L1 does this by displacing a novel mTORC1 interaction partner, namely the DDB1-CUL4 complex, identified in a previous study. This finding is very important because mutations of UCH-L1 have been seen in Parkinson’s disease, and UCH-L1 may also be involved in other brain disorders in which therapeutic inhibition of mTOR is already being investigated. Because of the well known role of mTOR in cancer, UCH-L1 also presents an exciting mechanism for cancer researchers.

Mentioned Articles

Ghosh P, Wu M, Zhang H, Sun H.
Cell Cycle. 2008 Feb 1;7(3):373-81. Epub 2007 Nov 2

Hussain S, Feldman AL, Das C, Ziesmer SC, Ansell SM, Galardy PJ.
Mol Cell Biol. 2013 Mar;33(6):1188-97. doi: 10.1128/MCB.01389-12. Epub 2013 Jan 7.

Wander SA, Hennessy BT, Slingerland JM.
Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy.
J Clin Invest. 2011 Apr;121(4):1231-41. doi: 10.1172/JCI44145. Epub 2011 Apr 1.

Weber JD, Gutmann DH.
Cell Cycle. 2012 Jan 15;11(2):236-48. doi: 10.4161/cc.11.2.19022. Epub 2012 Jan 15.

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