Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning

Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, 78957, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 05/2006; 173(2):279-89. DOI: 10.1083/jcb.200507119
Source: PubMed


Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development. However, in cells expressing tuberin, it is not known how repression of mTOR signaling is relieved to activate this pathway in response to growth factors and how hamartin participates in this process. We show that hamartin colocalizes with hypophosphorylated tuberin at the membrane, where tuberin exerts its GTPase-activating protein (GAP) activity to repress Rheb signaling. In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression. Phosphorylation of tuberin at serines 939 and 981 does not alter its intrinsic GAP activity toward Rheb but partitions tuberin to the cytosol, where it is bound by 14-3-3 proteins. Thus, tuberin bound by 14-3-3 in response to AKT phosphorylation is sequestered away from its membrane-bound activation partner (hamartin) and its target GTPase (Rheb) to relieve the growth inhibitory effects of this tumor suppressor.

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Available from: Andrew R Tee, Oct 01, 2015
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    • "Akt can phosphorylate TSC2 in response to growth factors (Inoki et al., 2002). This event is thought to favor TSC2 binding to protein 14-3-3, instead to TSC1, leading to TSC2 inhibition, to finally activate mTORC1 (Cai et al., 2006). "
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    ABSTRACT: Mechanistic target of Rapamycin (mTOR) pathway regulates essential processes directed to preserve cellular homeostasis, such as cell growth, proliferation, survival, protein synthesis and autophagy. Importantly, mTOR pathway deregulation has been related to many diseases. Indeed, it has become a hallmark in neurodegenerative disorders, since a fine-tuned regulation of mTOR activities is crucial for neuron function and survival. RTP801/REDD1/Dig2 has become one of the most puzzling regulators of mTOR. Although the mechanism is not completely understood, RTP801 inactivates mTOR and Akt via the tuberous sclerosis complex (TSC1/TSC2) in many cellular contexts. Intriguingly, RTP801 protects dividing cells from hypoxia or H2O2-induced apoptosis, while it sensitizes differentiated cells to stress. Based on experimental models of Parkinson's disease (PD), it has been proposed that at early stages of the disease, stress-induced RTP801 upregulation contributes to mTOR repression, in an attempt to maintain cell function and viability. However, if RTP801 elevation is sustained, it leads to neuron cell death by a sequential inhibition of mTOR and Akt. Here, we will review RTP801 deregulation of mTOR in a context of PD and other neurodegenerative disorders.
    Frontiers in Cellular Neuroscience 10/2014; 8:313. DOI:10.3389/fncel.2014.00313 · 4.29 Impact Factor
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    • "TSC1 and TSC2 are both required for full TSC1-TSC2 activity and whereas it is clear why the catalytic TSC2 subunit is essential, the exact role of TSC1 is less well defined. TSC1 stabilises TSC2 and prevents TSC2 ubiquitination and proteosomal degradation [6], helps maintain the TSC1-TSC2 complex in the correct intracellular localisation [7], [8] and regulates TSC1-TSC2 activity through diverse signalling pathways [9]. TSC1 and TSC2 form a stable complex due to interactions between the N-terminal domain (NTD) of TSC2 (amino acids 1 - 900) [10] and multiple regions in TSC1 [11], including a large predicted coiled coil close to the TSC1 C-terminus (amino acids 726 – 988) [2]. "
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    ABSTRACT: The TSC1-TSC2-TBC1D7 complex is an important negative regulator of the mechanistic target of rapamycin complex 1 that controls cell growth in response to environmental cues. Inactivating TSC1 and TSC2 mutations cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterised by the occurrence of benign tumours in various organs and tissues, notably the brain, skin and kidneys. TBC1D7 mutations have not been reported in TSC patients but homozygous inactivation of TBC1D7 causes megaencephaly and intellectual disability. Here, using an exon-specific deletion strategy, we demonstrate that some regions of TSC1 are not necessary for the core function of the TSC1-TSC2 complex. Furthermore, we show that the TBC1D7 binding site is encoded by TSC1 exon 22 and identify amino acid residues involved in the TSC1-TBC1D7 interaction.
    PLoS ONE 04/2014; 9(4):e93940. DOI:10.1371/journal.pone.0093940 · 3.23 Impact Factor
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    • "However, in light of the binding studies we did conduct together with the overlapping functional activities ILP3 and OEH exhibit, our data much more strongly suggest that OEH activates the insulin signaling pathway in ovaries independently of the MIR by binding to a different receptor. Insulin and TORC1 signaling both sense nutrient status but whether the two pathways are functionally linked is unsettled, given that some studies from vertebrates or D. melanogaster show activation of TORC1 in response to insulin signaling (Cai et al., 2006; Inoki et al., 2002; Manning et al., 2002; Potter et al., 2002) and others not (Dong and Pan, 2004; Hall et al., 2007; Radimerski et al., 2002). More recently, linkage between the insulin and TOR signaling pathways was shown to occur in the ovaries but not other tissues in D. melanogaster (Pallares-Cartes et al., 2012). "
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    ABSTRACT: Most mosquito species must feed on the blood of a vertebrate host to produce eggs. In the yellow fever mosquito, Aedes aegypti, blood feeding triggers medial neurosecretory cells in the brain to release insulin-like peptides (ILPs) and ovary ecdysteroidogenic hormone (OEH). Theses hormones thereafter directly induce the ovaries to produce ecdysteroid hormone (ECD), which activates the synthesis of yolk proteins in the fat body for uptake by oocytes. ILP3 stimulates ECD production by binding to the mosquito insulin receptor (MIR). In contrast, little is known about the mode of action of OEH, which is a member of a neuropeptide family called neuroparsin. Here we report that OEH is the only neuroparsin family member present in the Ae. aegypti genome and that other mosquitoes also encode only one neuroparsin gene. Immunoblotting experiments suggested that the full-length form of the peptide, which we call long OEH (lOEH), is processed into short OEH (sOEH). The importance of processing, however, remained unclear because a recombinant form of lOEH (rlOEH) and synthetic sOEH exhibited very similar biological activity. A series of experiments indicated that neither rlOEH nor sOEH bound to ILP3 or the MIR. Signaling studies further showed that ILP3 activated the MIR but rlOEH did not, yet both neuropeptides activated Akt, which is a marker for insulin pathway signaling. Our results also indicated that activation of TOR signaling in the ovaries required co-stimulation by amino acids and either ILP3 or rlOEH. Overall, we conclude that OEH activates the insulin signaling pathway independently of the MIR, and that insulin and TOR signaling in the ovaries is coupled.
    Insect biochemistry and molecular biology 09/2013; 43(12). DOI:10.1016/j.ibmb.2013.09.004 · 3.45 Impact Factor
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