The mTOR signalling pathway acts as a buffer, modulating energy expenditure in response to cellular environment. The mTORC1 complex is activated by the Rag proteins in response to amino acids and Rheb in response to growth factors, and inhibited by AMPK when glucose levels are low. Thus, when nutrient and growth factor availability is high, mTORC1 activates catabolic cell growth by stimulating protein translation, lipogenesis and de novo pyrimidine synthesis. When nutrient and growth factor availability is low, these energy consuming processes cease, and autophagy is de-repressed, allowing the cell to survive by recycling old proteins and organelles for energy. Thus, the mTOR pathway integrates multiple inputs to regulate multiple outcomes, so the cell can react appropriately to its environment.
Of further interest is that two well characterised kidney cancer genes regulate mTORC1 activity. The BHD protein, FLCN, was recently reported to activate mTORC1 signalling, via the Rag proteins, at the surface of lysosomes (Petit et al., 2013; Tsun et al., 2013). Furthermore, FLCN is known to interact with the mTORC1 inhibitor, AMPK (Baba et al., 2006). Secondly, the Tuberous sclerosis complex proteins TSC1 and TSC2 form a heterodimer, which inactivates Rheb, subsequently inhibiting mTORC1 activity. Recently, it was reported that TSC1, TSC2 and Rheb localise to peroxisomes where they inhibit mTORC1 signalling and activate autophagy in response to ROS production (Zhang et al., 2013). Furthermore, in HeLa cells mTORC1 is found to be sequestered in “stress granules” by DYRK3 under oxidative and osmotic stress (Wippich et al., 2013).
Taken together, these observations suggest that mTOR activity depends on where it is in the cell, as recently suggested by Benjamin and Hall (2013). The precise outcome of intracellular modulation of mTORC1’s activity is unknown. For example, it could be that mTORC1 carries out different activities in different cell microenvironments. Alternatively, overall mTORC1 activity in the cell could be integrated from its activity in multiple locations, thus controlling whether the whole cell is in a catabolic or anabolic state.
FLCN has also been implicated in numerous cell functions, such as RhoA signalling, apoptosis, autophagy and pluripotency. Quite how FLCN regulates all these processes is unknown, but it seems likely that – much like mTORC1 – it integrates multiple inputs to regulate multiple outcomes. While other factors, such as cell type, are likely to account for some of these different outcomes – for example, FLCN can only regulate pluripotency in pluripotent cells – cellular localisation is likely to play some role in allowing FLCN to act in multiple signalling pathways. Indeed, FLCN has been shown to activate mTOR signalling at the lysosome, to control cell adhesion at cell junctions, and to inhibit rRNA synthesis in the nucleolus.
Moreover, FLCN and its interacting proteins FNIP1 and FNIP2 carry non-canonical DENN domains, suggesting that they are membrane trafficking proteins. Thus it is possible that one of FLCN’s core functions might be to transport proteins to different sub-cellular locations, allowing such compartmentalised signalling to occur within cells. Indeed, FLCN is known to control the nuclear localisation of the transcription factors TFE3 and TFEB.
Determining the role of intracellular location in FLCN function will likely shed light on how FLCN controls so many different signalling pathways, and may suggest interventions to reverse or prevent the symptoms of BHD.
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Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR Jr, Linehan WM, Schmidt LS, & Zbar B (2006). Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America, 103 (42), 15552-7 PMID: 17028174
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Benjamin D, & Hall MN (2013). TSC on the peroxisome controls mTORC1. Nature cell biology, 15 (10), 1135-6 PMID: 24084861
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Petit CS, Roczniak-Ferguson A, & Ferguson SM (2013). Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. The Journal of cell biology, 202 (7), 1107-22 PMID: 24081491
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Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, & Sabatini DM (2013). The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1. Molecular cell PMID: 24095279
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Wippich F, Bodenmiller B, Trajkovska MG, Wanka S, Aebersold R, & Pelkmans L (2013). Dual specificity kinase DYRK3 couples stress granule condensation/dissolution to mTORC1 signaling. Cell, 152 (4), 791-805 PMID: 23415227
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Zhang J, Kim J, Alexander A, Cai S, Tripathi DN, Dere R, Tee AR, Tait-Mulder J, Di Nardo A, Han JM, Kwiatkowski E, Dunlop EA, Dodd KM, Folkerth RD, Faust PL, Kastan MB, Sahin M, & Walker CL (2013). A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nature cell biology, 15 (10), 1186-96 PMID: 23955302
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.