bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2022‒08‒14
23 papers selected by
Ralitsa Radostinova Madsen
University College London Cancer Institute

  1. Cancers (Basel). 2022 Jul 28. pii: 3666. [Epub ahead of print]14(15):
      PTEN is the second most highly mutated tumor suppressor in cancer, following only p53. The PTEN protein functions as a phosphatase with lipid- and protein-phosphatase activity. PTEN-lipid-phosphatase activity dephosphorylates PIP3 to form PIP2, and it then antagonizes PI3K and blocks the activation of AKT, while its protein-phosphatase activity dephosphorylates different protein substrates and plays various roles in tumorigenesis. Here, we review the PTEN mutations and protein-phosphatase substrates in tumorigenesis and metastasis. Our purpose is to clarify how PTEN protein phosphatase contributes to its tumor-suppressive functions through PI3K-independent activities.
    Keywords:  PTEN; PTEN lipid phosphatase; PTEN protein phosphatase; PTEN protein substrate; metastasis; mutation; tumorigenesis
  2. mBio. 2022 Aug 10. e0104222
      The protein kinase Akt broadly impacts many cellular processes, including mRNA translation, metabolism, apoptosis, and stress responses. Inhibition of phosphatidylinositol 3-kinase (PI3K), a lipid kinase pivotal to Akt activation, triggers various herpesviruses to reactivate from latency. Hence, decreased Akt activity may promote lytic replication. Here, we show that Akt accumulates in an inactive form during human cytomegalovirus (HCMV) infection of permissive fibroblasts, as indicated by hypophosphorylation of sites that activate Akt, decreased phosphorylation of PRAS40, and pronounced nuclear localization of FoxO3a, a substrate that remains cytoplasmic when Akt is active. HCMV strongly activates mTORC1 during lytic infection, suggesting a potential mechanism for Akt inactivation, since mTORC1 negatively regulates PI3K. However, we were surprised to observe that constitutive Akt activity, provided by expression of Akt fused to a myristoylation signal (myr-Akt), caused a 1-log decrease in viral replication, accompanied by defects in viral DNA synthesis and late gene expression. These results indicated that Akt inactivation is required for efficient viral replication, prompting us to address which Akt substrates underpin this requirement. Interestingly, we found that short interfering RNA knockdown of FoxO3a, but not FoxO1, phenocopied the defects caused by myr-Akt, corroborating a role for FoxO3a. Accordingly, a chimeric FoxO3a-estrogen receptor fusion protein, in which nuclear localization is regulated by 4-hydroxytamoxifen instead of Akt, reversed the replication defects caused by myr-Akt. Collectively, our results reveal a role for FoxO transcription factors in HCMV lytic replication and argue that this single class of Akt substrates underpins the requirement for Akt inactivation during productive infection. IMPORTANCE Evidence from diverse herpesvirus infection models suggests that the PI3K/Akt signaling pathway suppresses reactivation from latency and that inactivation of the pathway stimulates viral lytic replication. Here, we show that Akt accumulates in an inactive state during HCMV infection of lytically permissive cells while the presence of constitutive Akt activity causes substantial viral replication defects. Although Akt phosphorylates a diverse array of cellular substrates, we identify an important role for the Forkhead box class O transcription factors. Our findings show that when FoxO3a nuclear localization is decoupled from its negative regulation by Akt, the viral replication defects observed in the presence of constitutively active Akt are reversed. Collectively, our results reveal that HCMV inactivates Akt to promote the nuclear localization of FoxO transcription factors, which strongly implies that FoxOs play critical roles in transactivating cellular and/or viral genes during infection.
    Keywords:  AKT signaling; cytomegalovirus; herpesviruses; human herpesviruses; metabolism; protein kinases; stress response; transcription factors
  3. Nat Commun. 2022 Aug 09. 13(1): 4665
      Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that negatively regulate mTOR complex 1 (mTORC1) signaling. Current treatment strategies focus on mTOR inhibition with rapamycin and its derivatives. While effective at improving some aspects of TSC, chronic rapamycin inhibits both mTORC1 and mTORC2 and is associated with systemic side-effects. It is currently unknown which mTOR complex is most relevant for TSC-related brain phenotypes. Here we used genetic strategies to selectively reduce neuronal mTORC1 or mTORC2 activity in mouse models of TSC. We find that reduction of the mTORC1 component Raptor, but not the mTORC2 component Rictor, rebalanced mTOR signaling in Tsc1 knock-out neurons. Raptor reduction was sufficient to improve several TSC-related phenotypes including neuronal hypertrophy, macrocephaly, impaired myelination, network hyperactivity, and premature mortality. Raptor downregulation represents a promising potential therapeutic intervention for the neurological manifestations of TSC.
  4. Mol Cell Endocrinol. 2022 Aug 05. pii: S0303-7207(22)00187-3. [Epub ahead of print] 111739
      The insulin receptor (IR) gene undergoes differential splicing generating two IR isoforms, IR-A and IR-B. The roles of IR-A in cancer and of IR-B in metabolic regulation are well known but the molecular mechanisms responsible for their different biological effects are poorly understood. We aimed to identify different or similar protein substrates and signaling linked to each IR isoforms. We employed mouse fibroblasts lacking IGF1R gene and expressing exclusively either IR-A or IR-B. By proteomic analysis a total of 2530 proteins were identified and quantified. Proteins and pathways mostly associated with insulin-activated IR-A were involved in cancer, stemness and interferon signaling. Instead, proteins and pathways associated with insulin-stimulated IR-B-expressing cells were mostly involved in metabolic or tumor suppressive functions. These results show that IR-A and IR-B recruit partially different multiprotein complexes in response to insulin, suggesting partially different functions of IR isoforms in physiology and in disease.
    Keywords:  Cancer; Insulin; Insulin receptor isoforms; Insulin receptor signaling; Insulin receptor substrates; Quantitative proteomics
  5. J Cell Sci. 2022 Aug 10. pii: jcs.259686. [Epub ahead of print]
      Signaling through the platelet-derived growth factor receptors (PDGFRs) plays a critical role in multiple cellular processes during development. The two PDGFRs, PDGFR and PDGFR, dimerize to form homodimers and/or heterodimers. Here, we overcome previous limitations in studying PDGFR dimer-specific dynamics by generating cell lines stably expressing C-terminal fusions of each PDGFR with bimolecular fluorescence complementation (BiFC) fragments corresponding to the N-terminal or C-terminal regions of the Venus fluorescent protein. We find that PDGFR receptors homodimerize more quickly than PDGFR receptors in response to PDGF ligand, with increased levels of autophosphorylation. Further, we demonstrate that PDGFR homodimers are trafficked and degraded more quickly, while PDGFR homodimers are more likely to be recycled back to the cell membrane. We show that PDGFR homodimer activation results in a greater amplitude of phospho-ERK1/2 and phospho-AKT signaling, as well as increased proliferation and migration. Finally, we demonstrate that inhibition of clathrin-mediated endocytosis leads to changes in cellular trafficking and downstream signaling, particularly for PDGFRa homodimers. Collectively, our findings provide significant insight into how biological specificity is introduced to generate unique responses downstream of PDGFR engagement.
    Keywords:  Migration; PDGFRalpha; PDGFRbeta; Proliferation; Signaling; Trafficking
  6. Cell Rep. 2022 Aug 09. pii: S2211-1247(22)00990-1. [Epub ahead of print]40(6): 111177
      Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profile selinexor signaling responses using phosphoproteomics in primary AML patient samples and cell lines. Functional phosphosite scoring reveals that p53 function is required for selinexor sensitivity consistent with enhanced efficacy of selinexor in combination with the MDM2 inhibitor nutlin-3a. Moreover, combining selinexor with the AKT inhibitor MK-2206 overcomes dysregulated AKT-FOXO3 signaling in resistant cells, resulting in synergistic anti-proliferative effects. Using high-throughput spatial proteomics to profile subcellular compartments, we measure global proteome and phospho-proteome dynamics, providing direct evidence of nuclear translocation of FOXO3 upon combination treatment. Our data demonstrate the potential of phosphoproteomics and functional phosphorylation site scoring to successfully pinpoint key targetable signaling hubs for rational drug combinations.
    Keywords:  CP: Cancer; CP: Molecular biology; MK-2206; acute myeloid leukemia; combination therapy; drug resistance; functional scoring; mass spectrometry; nutlin-3a; phosphoproteomics; selinexor; subcellular proteomics
  7. PLoS One. 2022 ;17(8): e0269272
      Single-cell measurements have revolutionized our understanding of heterogeneity in cellular response. However, there is no universally comparable way to assess single-cell measurement quality. Here, we show how information theory can be used to assess and compare single-cell measurement quality in bits, which provides a universally comparable metric for information content. We anticipate that the experimental and theoretical approaches we show here will generally enable comparisons of quality between any single-cell measurement methods.
  8. Nat Commun. 2022 Aug 10. 13(1): 4685
      The protein kinase mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and proliferation, supporting anabolic reactions and inhibiting catabolic pathways like autophagy. Its hyperactivation is a frequent event in cancer promoting tumor cell proliferation. Several intracellular membrane-associated mTORC1 pools have been identified, linking its function to distinct subcellular localizations. Here, we characterize the N-terminal kinase-like protein SCYL1 as a Golgi-localized target through which mTORC1 controls organelle distribution and extracellular vesicle secretion in breast cancer cells. Under growth conditions, SCYL1 is phosphorylated by mTORC1 on Ser754, supporting Golgi localization. Upon mTORC1 inhibition, Ser754 dephosphorylation leads to SCYL1 displacement to endosomes. Peripheral, dephosphorylated SCYL1 causes Golgi enlargement, redistribution of early and late endosomes and increased extracellular vesicle release. Thus, the mTORC1-controlled phosphorylation status of SCYL1 is an important determinant regulating subcellular distribution and function of endolysosomal compartments. It may also explain the pathophysiology underlying human genetic diseases such as CALFAN syndrome, which is caused by loss-of-function of SCYL1.
  9. Mol Cell Proteomics. 2022 Aug 06. pii: S1535-9476(22)00087-1. [Epub ahead of print] 100279
      Data-independent acquisition (DIA) methods have become increasingly attractive in mass spectrometry (MS)-based proteomics, because they enable high data completeness and a wide dynamic range. Recently, we combined DIA with parallel accumulation - serial fragmentation (dia-PASEF) on a Bruker trapped ion mobility separated (TIMS) quadrupole time-of-flight (TOF) mass spectrometer. This requires alignment of the ion mobility separation with the downstream mass selective quadrupole, leading to a more complex scheme for dia-PASEF window placement compared to DIA. To achieve high data completeness and deep proteome coverage, here we employ variable isolation windows that are placed optimally depending on precursor density in the m/z and ion mobility plane. This Automatic Isolation Design procedure is implemented in the freely available py_diAID package. In combination with in-depth project-specific proteomics libraries and the Evosep LC system, we reproducibly identified over 7,700 proteins in a human cancer cell line in 44 minutes with quadruplicate single-shot injections at high sensitivity. Even at a throughput of 100 samples per day (11 minutes LC gradients), we consistently quantified more than 6,000 proteins in mammalian cell lysates by injecting four replicates. We found that optimal dia-PASEF window placement facilitates in-depth phosphoproteomics with very high sensitivity, quantifying more than 35,000 phosphosites in a human cancer cell line stimulated with an epidermal growth factor (EGF) in triplicate 21 minutes runs. This covers a substantial part of the regulated phosphoproteome with high sensitivity, opening up for extensive systems-biological studies.
    Keywords:  PASEF; TIMS; data-independent acquisition; phosphoproteomics; systems biology
  10. Sci Signal. 2022 Aug 09. 15(746): eadc9816
      Although oncogenic driver mutations in RAS occur in 20% of cancers, heterogeneity in the biologic outputs of different RAS mutants has hampered efforts to develop effective treatments for RAS-mutated cancers. In this issue of Science Signaling, Huynh et al. show that even among KRASQ61 mutants, the specific amino acid that is substituted substantially affects mutant KRAS biologic activity and oncogenicity.
  11. Trends Biotechnol. 2022 Aug 03. pii: S0167-7799(22)00191-3. [Epub ahead of print]
      Technological advances have led to the emergence of lineage tracers, but signal recorders for mammalian systems have remained elusive. Kempton et al. have developed a Cas12a base-editing signal recorder capable of capturing diverse signals and operating in various experimental designs. The recorder enables new opportunities to chronicle cellular history.
    Keywords:  CRISPR-Cas12a; DNA mutation; base editor; molecular recording; signaling
  12. Nat Commun. 2022 Aug 11. 13(1): 4528
      Pten is one of the most frequently mutated tumour suppressor gene in cancer. PTEN is generally altered in invasive cancers such as glioblastomas, but its function in collective cell migration and invasion is not fully characterised. Herein, we report that the loss of PTEN increases cell speed during collective migration of non-tumourous cells both in vitro and in vivo. We further show that loss of PTEN promotes LKB1-dependent phosphorylation and activation of the major metabolic regulator AMPK. In turn AMPK increases VASP phosphorylation, reduces VASP localisation at cell-cell junctions and decreases the interjunctional transverse actin arcs at the leading front, provoking a weakening of cell-cell contacts and increasing migration speed. Targeting AMPK activity not only slows down PTEN-depleted cells, it also limits PTEN-null glioblastoma cell invasion, opening new opportunities to treat glioblastoma lethal invasiveness.
  13. Nat Commun. 2022 Aug 11. 13(1): 4724
      As CRISPR-based therapies enter the clinic, evaluation of safety remains a critical and active area of study. Here, we employ a clinical next generation sequencing (NGS) workflow to achieve high sequencing depth and detect ultra-low frequency variants across exons of genes associated with cancer, all exons, and genome wide. In three separate primary human hematopoietic stem and progenitor cell (HSPC) donors assessed in technical triplicates, we electroporated high-fidelity Cas9 protein targeted to three loci (AAVS1, HBB, and ZFPM2) and harvested genomic DNA at days 4 and 10. Our results demonstrate that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants and that even a single SNP in a gRNA spacer sequence is sufficient to eliminate Cas9 off-target activity in primary, repair-competent human HSPCs.
  14. J Clin Endocrinol Metab. 2022 Aug 12. pii: dgac475. [Epub ahead of print]
    Keywords:  Adrenal; Hyperandrogenism; Insulin Receptor; Insulin resistance; Lipodystrophy; Ovaries
  15. Cell Biosci. 2022 Aug 08. 12(1): 124
      BACKGROUND: Targeting the HGF/MET signaling pathway has been a viable therapeutic strategy for various cancer types due to hyperactivation of HGF/MET axis occurs frequently that leads to detrimental cancer progression and recurrence. Deciphering novel molecule mechanisms underlying complex HGF/MET signaling network is therefore critical to development of effective therapeutics for treating MET-dependent malignancies.RESULTS: Using isobaric mass tag-based quantitative proteomics approach, we identified IFITM3, an interferon-induced transmembrane protein that was highly expressed in micro-dissected gastric cancer (GC) tumor regions relative to adjacent non-tumor epithelia. Analyses of GC clinical specimens revealed that expression IFITM3 was closely correlated to advanced pathological stages. IFITM3 has been reported as a PIP3 scaffold protein that promotes PI3K signaling. In present study, we unprecedentedly unraveled that IFITM3 associated with MET and AKT to facilitate HGF/MET mediated AKT signaling crosstalk in suppressing FOXO3, consequently leading to c-MYC mediated GC progression. In addition, gene ontology analyses of the clinical GC cohort revealed significant correlation between IFITM3-associated genes and targets of c-MYC, which is a crucial downstream effector of HGF/MET pathway in cancer progression. Moreover, we demonstrated ectopic expression of IFITM3 suppressed FOXO3 expression, consequently led to c-MYC induction to promote tumor growth, cell metastasis, cancer stemness as well as chemoresistance. Conversely, depletion of IFITM3 resulted in suppression of HGF triggered cellular growth and migration via inhibition of AKT/c-MYC signaling in GC.
    CONCLUSIONS: In summary, our present study unveiled a novel regulatory mechanism for c-MYC-driven oncogenesis underlined by IFITM3-mediated signaling crosstalk between MET associated AKT signaling cascade.
    Keywords:  Cancer stemness; FOXO3; Gastric cancer; IFITM3; MET; c-MYC; iTRAQ quantitative proteomic analysis
  16. Open Biol. 2022 Aug;12(8): 220149
      Organ functions are highly specialized and interdependent. Secreted factors regulate organ development and mediate homeostasis through serum trafficking and inter-organ communication. Enzyme-catalysed proximity labelling enables the identification of proteins within a specific cellular compartment. Here, we report a BirA*G3 mouse strain that enables CRE-dependent promiscuous biotinylation of proteins trafficking through the endoplasmic reticulum. When broadly activated throughout the mouse, widespread labelling of proteins was observed within the secretory pathway. Streptavidin affinity purification and peptide mapping by quantitative mass spectrometry (MS) proteomics revealed organ-specific secretory profiles and serum trafficking. As expected, secretory proteomes were highly enriched for signal peptide-containing proteins, highlighting both conventional and non-conventional secretory processes, and ectodomain shedding. Lower-abundance proteins with hormone-like properties were recovered and validated using orthogonal approaches. Hepatocyte-specific activation of BirA*G3 highlighted liver-specific biotinylated secretome profiles. The BirA*G3 mouse model demonstrates enhanced labelling efficiency and tissue specificity over viral transduction approaches and will facilitate a deeper understanding of secretory protein interplay in development, and in healthy and diseased adult states.
    Keywords:  BirA; TurboID; inter-organ communication; proximity-labelling; secretome; serum proteins
  17. Nat Commun. 2022 Aug 09. 13(1): 4674
      The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.
  18. Nat Genet. 2022 Aug 11.
      We explored human induced pluripotent stem cells (hiPSCs) derived from different tissues to gain insights into genomic integrity at single-nucleotide resolution. We used genome sequencing data from two large hiPSC repositories involving 696 hiPSCs and daughter subclones. We find ultraviolet light (UV)-related damage in ~72% of skin fibroblast-derived hiPSCs (F-hiPSCs), occasionally resulting in substantial mutagenesis (up to 15 mutations per megabase). We demonstrate remarkable genomic heterogeneity between independent F-hiPSC clones derived during the same round of reprogramming due to oligoclonal fibroblast populations. In contrast, blood-derived hiPSCs (B-hiPSCs) had fewer mutations and no UV damage but a high prevalence of acquired BCOR mutations (26.9% of lines). We reveal strong selection pressure for BCOR mutations in F-hiPSCs and B-hiPSCs and provide evidence that they arise in vitro. Directed differentiation of hiPSCs and RNA sequencing showed that BCOR mutations have functional consequences. Our work strongly suggests that detailed nucleotide-resolution characterization is essential before using hiPSCs.
  19. Methods Cell Biol. 2022 ;pii: S0091-679X(22)00053-X. [Epub ahead of print]171 111-125
      The heterogeneity of breast tumors is a major factor in the development, progression, and therapeutic response of breast cancer. In terms of therapy resistance, a subset of tumor cells commonly referred to as cancer stem cells (CSCs) or tumor initiating cells (TICs) have a prominent role. These cells have inherent increased tumorigenicity, self-renewal and differentiation capacity, and mechanisms for chemotherapy and radiation resistance. The importance of CSCs/TICs in cancer makes isolating and studying these cells via reliable methods critical. CSCs/TICs can be enriched for by discrete markers. Increased aldehyde dehydrogenase (ALDH) activity as detected by the AldefluorTM assay is a commonly used method. In this chapter, we describe the detailed methods for identification and isolation of putative CSCs/TICs from cultured cells and xenografted breast tumors using the AldefluorTM assay and describe the importance of the ALDH isoforms in breast cancer.
    Keywords:  ALDH1A1; ALDH1A3; Aldefluor assay; Breast cancer; Cancer stem cells; Fluorescent associated cell sorting (FACS)
  20. Nat Commun. 2022 Aug 09. 13(1): 4678
      There are only a few platforms that integrate multiple omics data types, bioinformatics tools, and interfaces for integrative analyses and visualization that do not require programming skills. Here we present iLINCS ( ), an integrative web-based platform for analysis of omics data and signatures of cellular perturbations. The platform facilitates mining and re-analysis of the large collection of omics datasets (>34,000), pre-computed signatures (>200,000), and their connections, as well as the analysis of user-submitted omics signatures of diseases and cellular perturbations. iLINCS analysis workflows integrate vast omics data resources and a range of analytics and interactive visualization tools into a comprehensive platform for analysis of omics signatures. iLINCS user-friendly interfaces enable execution of sophisticated analyses of omics signatures, mechanism of action analysis, and signature-driven drug repositioning. We illustrate the utility of iLINCS with three use cases involving analysis of cancer proteogenomic signatures, COVID 19 transcriptomic signatures and mTOR signaling.
  21. Elife. 2022 Aug 08. pii: e78923. [Epub ahead of print]11
      Monitoring autophagic flux is necessary for most autophagy studies. The autophagic flux assays currently available for mammalian cells are generally complicated and do not yield highly quantitative results. Yeast autophagic flux is routinely monitored with the GFP-based processing assay, whereby the amount of GFP proteolytically released from GFP-containing reporters (e.g., GFP-Atg8), detected by immunoblotting, reflects autophagic flux. However, this simple and effective assay is typically inapplicable to mammalian cells because GFP is efficiently degraded in lysosomes while the more proteolytically resistant RFP accumulates in lysosomes under basal conditions. Here, we report a HaloTag (Halo)-based reporter processing assay to monitor mammalian autophagic flux. We found that Halo is sensitive to lysosomal proteolysis but becomes resistant upon ligand binding. When delivered into lysosomes by autophagy, pulse-labeled Halo-based reporters (e.g., Halo-LC3 and Halo-GFP) are proteolytically processed to generate Haloligand when delivered into lysosomes by autophagy. Hence, the amount of free Haloligand detected by immunoblotting or in-gel fluorescence imaging reflects autophagic flux. We demonstrate the applications of this assay by monitoring the autophagy pathways, macroautophagy, selective autophagy, and even bulk nonselective autophagy. With the Halo-based processing assay, mammalian autophagic flux and lysosome-mediated degradation can be monitored easily and precisely.
    Keywords:  cell biology; human; mouse
  22. Proc Natl Acad Sci U S A. 2022 Aug 16. 119(33): e2121040119
      Regulation of firing rate homeostasis constitutes a fundamental property of central neural circuits. While intracellular Ca2+ has long been hypothesized to be a feedback control signal, the molecular machinery enabling a network-wide homeostatic response remains largely unknown. We show that deletion of insulin-like growth factor-1 receptor (IGF-1R) limits firing rate homeostasis in response to inactivity, without altering the distribution of baseline firing rates. The deficient firing rate homeostatic response was due to disruption of both postsynaptic and intrinsic plasticity. At the cellular level, we detected a fraction of IGF-1Rs in mitochondria, colocalized with the mitochondrial calcium uniporter complex (MCUc). IGF-1R deletion suppressed transcription of the MCUc members and burst-evoked mitochondrial Ca2+ (mitoCa2+) by weakening mitochondria-to-cytosol Ca2+ coupling. Overexpression of either mitochondria-targeted IGF-1R or MCUc in IGF-1R-deficient neurons was sufficient to rescue the deficits in burst-to-mitoCa2+ coupling and firing rate homeostasis. Our findings indicate that mitochondrial IGF-1R is a key regulator of the integrated homeostatic response by tuning the reliability of burst transfer by MCUc. Based on these results, we propose that MCUc acts as a homeostatic Ca2+ sensor. Faulty activation of MCUc may drive dysregulation of firing rate homeostasis in aging and in brain disorders associated with aberrant IGF-1R/MCUc signaling.
    Keywords:  IGF-1 receptor; MCU; firing rate homeostasis; homeostatic plasticity; mitochonria
  23. F1000Res. 2022 ;11 420
      Human and animal cell lines serve as model systems in a wide range of life sciences such as cancer and infection research or drug screening. Reproducible data are highly dependent on authenticated, contaminant-free cell lines, no better delivered than by the official and certified biorepositories. Offering a web portal to high-throughput information on these model systems will facilitate working with and comparing to these references by data otherwise dispersed at different sources. We here provide DSMZCellDive to access a comprehensive data source on human and animal cell lines, freely available at A wide variety of data sources are generated such as RNA-seq transcriptome data and STR (short tandem repeats) profiles. Several starting points ease entering the database via browsing, searching or visualising. This web tool is designed for further expansion on meta and high-throughput data to be generated in future. Explicated examples for the power of this novel tool include analysis of B-cell differentiation markers, homeo-oncogene expression, and measurement of genomic loss of heterozygosities by an enlarged STR panel of 17 loci. Sharing the data on cell lines by the biorepository itself will be of benefit to the scientific community  since it (1) supports the selection of appropriate model cell lines, (2) ensures reliability, (3) avoids misleading data, (4) saves on additional experimentals, and (5) serves as reference for genomic and gene expression data.
    Keywords:  DSMZ; HLA; LL-100; RNA-seq; STR; homeobox; human and animal cell lines; leukemia; lymphoma; omics data