bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022–07–31
eight papers selected by
  1. Amiodarone-sirolimus interaction in a neonate with tuberous sclerosis complex.
  2. Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2.
  3. Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer.
  4. Beyond controlling cell size: functional analyses of S6K in tumorigenesis.
  5. A sphingolipid-mTORC1 nutrient-sensing pathway regulates animal development by an intestinal peroxisome relocation-based gut-brain crosstalk.
  6. Sensing of the non-essential amino acid tyrosine governs the response to protein restriction in Drosophila.
  7. Manganese is a physiologically relevant TORC1 activator in yeast and mammals.
  8. Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy.
  1. Cardiol Young. 2022 Jul 28. 1-2
    Amiodarone-sirolimus interaction in a neonate with tuberous sclerosis complex.
    Daniel Ebrahimi-Fakhari, Hans G Kehl, Heymut Omran.
      
    Keywords:  Cardiac tumour; TSC; interaction; mTOR inhibitor; rapamycin; rhabdomyoma; tuberous sclerosis complex
    DOI:  https://doi.org/10.1017/S1047951122002372
  2. Elife. 2022 Jul 26. pii: e75398. [Epub ahead of print]11
    Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2.
    Polina Kosillo, Kamran M Ahmed, Erin E Aisenberg, Vasiliki Karalis, Bradley M Roberts, Stephanie J Cragg, Helen S Bateup.
      The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties, and whether they have similar or distinct functions is unknown. Here, we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. Disruption of both mTOR complexes leads to pronounced deficits in dopamine release demonstrating the importance of balanced mTORC1 and mTORC2 signaling for dopaminergic function.
    Keywords:  TSC; dopamine neurons; mTORC1; mTORC2; mouse; neuroscience; raptor; rictor
    DOI:  https://doi.org/10.7554/eLife.75398
  3. Biomolecules. 2022 Jul 01. pii: 928. [Epub ahead of print]12(7):
    Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer.
    Sarah J Backe, Rebecca A Sager, Katherine A Meluni, Mark R Woodford, Dimitra Bourboulia, Mehdi Mollapour.
      Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients. Many early observations of the roles of FNIP1, FNIP2, and Tsc1 suggested functions independent of FLCN and Tsc2 but have not been fully delineated. Given the broad cellular impact of Hsp90-dependent signaling, it is possible to explain the cellular activities of these new co-chaperones by their influence on Hsp90 function. Here, we review the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discuss the potential downstream impact of this regulation on normal cellular function and in human diseases.
    Keywords:  FNIP1; FNIP2; Tsc1 (hamartin); Tsc2 (tuberin); cancer; co-chaperones; heat shock protein 90 (Hsp90); kidney cancer; renal cell carcinoma; tuberous sclerosis complex (TSC)
    DOI:  https://doi.org/10.3390/biom12070928
  4. Cell Death Dis. 2022 Jul 25. 13(7): 646
    Beyond controlling cell size: functional analyses of S6K in tumorigenesis.
    Xueji Wu, Wei Xie, Wenxuan Xie, Wenyi Wei, Jianping Guo.
      As a substrate and major effector of the mammalian target of rapamycin complex 1 (mTORC1), the biological functions of ribosomal protein S6 kinase (S6K) have been canonically assigned for cell size control by facilitating mRNA transcription, splicing, and protein synthesis. However, accumulating evidence implies that diverse stimuli and upstream regulators modulate S6K kinase activity, leading to the activation of a plethora of downstream substrates for distinct pathobiological functions. Beyond controlling cell size, S6K simultaneously plays crucial roles in directing cell apoptosis, metabolism, and feedback regulation of its upstream signals. Thus, we comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, clinical relevance, and candidate inhibitors for S6K and shed light on S6K as a potential therapeutic target for cancers.
    DOI:  https://doi.org/10.1038/s41419-022-05081-4
  5. Cell Rep. 2022 Jul 26. pii: S2211-1247(22)00949-4. [Epub ahead of print]40(4): 111140
    A sphingolipid-mTORC1 nutrient-sensing pathway regulates animal development by an intestinal peroxisome relocation-based gut-brain crosstalk.
    Na Li, Beilei Hua, Qing Chen, Fukang Teng, Meiyu Ruan, Mengnan Zhu, Li Zhang, Yinbo Huo, Hongqin Liu, Min Zhuang, Huali Shen, Huanhu Zhu.
      The mTOR-dependent nutrient-sensing and response machinery is the central hub for animals to regulate their cellular and developmental programs. However, equivalently pivotal nutrient and metabolite signals upstream of mTOR and developmental-regulatory signals downstream of mTOR are not clear, especially at the organism level. We previously showed glucosylceramide (GlcCer) acts as a critical nutrient and metabolite signal for overall amino acid levels to promote development by activating the intestinal mTORC1 signaling pathway. Here, through a large-scale genetic screen, we find that the intestinal peroxisome is critical for antagonizing the GlcCer-mTORC1-mediated nutrient signal. Mechanistically, GlcCer deficiency, inactive mTORC1, or prolonged starvation relocates intestinal peroxisomes closer to the apical region in a kinesin- and microtubule-dependent manner. Those apical accumulated peroxisomes further release peroxisomal-β-oxidation-derived glycolipid hormones that target chemosensory neurons and downstream nuclear hormone receptor DAF-12 to arrest the animal development. Our data illustrate a sophisticated gut-brain axis that predominantly orchestrates nutrient-sensing-dependent development in animals.
    Keywords:  C.elegans; CP: Cell biology; ascaroside; diapause; glucosylceramide; gut-brain axis; hormone; mTOR pathway; metabolism; nutrient sensing; peroxisome repositioning
    DOI:  https://doi.org/10.1016/j.celrep.2022.111140
  6. Nat Metab. 2022 Jul;4(7): 944-959
    Sensing of the non-essential amino acid tyrosine governs the response to protein restriction in Drosophila.
    Hina Kosakamoto, Naoki Okamoto, Hide Aikawa, Yuki Sugiura, Makoto Suematsu, Ryusuke Niwa, Masayuki Miura, Fumiaki Obata.
      The intake of dietary protein regulates growth, metabolism, fecundity and lifespan across various species, which makes amino acid (AA)-sensing vital for adaptation to the nutritional environment. The general control nonderepressible 2 (GCN2)-activating transcription factor 4 (ATF4) pathway and the mechanistic target of rapamycin complex 1 (mTORC1) pathway are involved in AA-sensing. However, it is not fully understood which AAs regulate these two pathways in living animals and how they coordinate responses to protein restriction. Here we show in Drosophila that the non-essential AA tyrosine (Tyr) is a nutritional cue in the fat body necessary and sufficient for promoting adaptive responses to a low-protein diet, which entails reduction of protein synthesis and mTORC1 activity and increased food intake. This adaptation is regulated by dietary Tyr through GCN2-independent induction of ATF4 target genes in the fat body. This study identifies the Tyr-ATF4 axis as a regulator of the physiological response to a low-protein diet and sheds light on the essential function of a non-essential nutrient.
    DOI:  https://doi.org/10.1038/s42255-022-00608-7
  7. Elife. 2022 Jul 29. pii: e80497. [Epub ahead of print]11
    Manganese is a physiologically relevant TORC1 activator in yeast and mammals.
    Raffaele Nicastro, Hélène Gaillard, Laura Zarzuela, Marie-Pierre Péli-Gulli, Elisabet Fernández-García, Mercedes Tomé, Néstor García-Rodríguez, Raúl V Durán, Claudio De Virgilio, Ralf Erik Wellinger.
      The essential biometal manganese (Mn) serves as a cofactor for several enzymes that are crucial for the prevention of human diseases. Whether intracellular Mn levels may be sensed and modulate intracellular signaling events has so far remained largely unexplored. The highly conserved target of rapamycin complex 1 (TORC1, mTORC1 in mammals) protein kinase requires divalent metal cofactors such as magnesium (Mg2+) to phosphorylate effectors as part of a homeostatic process that coordinates cell growth and metabolism with nutrient and/or growth factor availability. Here, our genetic approaches reveal that TORC1 activity is stimulated in vivo by elevated cytoplasmic Mn levels, which can be induced by loss of the Golgi-resident Mn2+ transporter Pmr1 and which depend on the natural resistance-associated macrophage protein (NRAMP) metal ion transporters Smf1 and Smf2. Accordingly, genetic interventions that increase cytoplasmic Mn2+ levels antagonize the effects of rapamycin in triggering autophagy, mitophagy, and Rtg1-Rtg3-dependent mitochondrion-to-nucleus retrograde signaling. Surprisingly, our in vitro protein kinase assays uncovered that Mn2+ activates TORC1 substantially better than Mg2+, which is primarily due to its ability to lower the Km for ATP, thereby allowing more efficient ATP coordination in the catalytic cleft of TORC1. These findings, therefore, provide both a mechanism to explain our genetic observations in yeast and a rationale for how fluctuations in trace amounts of Mn can become physiologically relevant. Supporting this notion, TORC1 is also wired to feedback control mechanisms that impinge on Smf1 and Smf2. Finally, we also show that Mn2+-mediated control of TORC1 is evolutionarily conserved in mammals, which may prove relevant for our understanding of the role of Mn in human diseases.
    Keywords:  NRAMP transporter; S. cerevisiae; TORC1; autophagy; biochemistry; chemical biology; genetics; genomics; human; manganese; mitophagy
    DOI:  https://doi.org/10.7554/eLife.80497
  8. Cancers (Basel). 2022 Jul 11. pii: 3374. [Epub ahead of print]14(14):
    Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy.
    Leslie Cuellar-Vite, Kristen L Weber-Bonk, Fadi W Abdul-Karim, Christine N Booth, Ruth A Keri.
      The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast cancer subtypes. We sought to discover collateral sensitivities to mTORC1 inhibition that could be exploited to improve therapeutic response. Using a mouse model of breast cancer that is intrinsically resistant to mTORC1 inhibition, we found that rapamycin alters the expression of numerous extracellular matrix genes, suggesting a potential role for integrins/FAK in controlling mTORC1-inhibitor efficacy. FAK activation was also inversely correlated with rapamycin response in breast cancer cell lines. Supporting its potential utility in patients, FAK activation was observed in >50% of human breast cancers. While blocking FAK in mouse models of breast cancer that are highly responsive to rapamycin had no impact on tumor growth, FAK inhibition sensitized rapamycin-resistant tumors to mTORC1 inhibition. These data reveal an innate dependency on FAK when mTORC1 signaling is lost in tumors that are resistant to mTORC1 inhibitors. They also suggest a precision medicine approach to improving mTORC1 inhibitor efficacy in resistant cancers by suppressing FAK signaling.
    Keywords:  FAK; TNBC; collateral sensitivity; defactinib; focal adhesion kinase; intrinsic resistance; mTORC1; rapamycin; triple negative breast cancer
    DOI:  https://doi.org/10.3390/cancers14143374
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