scholarly journals Endosomal entry regulates Notch receptor activation in Drosophila melanogaster

2008 ◽  
Vol 180 (4) ◽  
pp. 755-762 ◽  
Author(s):  
Thomas Vaccari ◽  
Han Lu ◽  
Ritu Kanwar ◽  
Mark E. Fortini ◽  
David Bilder
Keyword(s):  
Drosophila Melanogaster ◽  
Notch Pathway ◽  
Receptor Activation ◽  
Notch Receptor ◽  
Animal Development ◽  
Cell Proliferation And Differentiation ◽  
Pathway Activation ◽  
Proliferation And Differentiation ◽  
Low Efficiency ◽  
Endocytic Compartments

Signaling through the transmembrane receptor Notch is widely used throughout animal development and is a major regulator of cell proliferation and differentiation. During canonical Notch signaling, internalization and recycling of Notch ligands controls signaling activity, but the involvement of endocytosis in activation of Notch itself is not well understood. To address this question, we systematically assessed Notch localization, processing, and signaling in a comprehensive set of Drosophila melanogaster mutants that block access of cargo to different endocytic compartments. We find that γ-secretase cleavage and signaling of endogenous Notch is reduced in mutants that impair entry into the early endosome but is enhanced in mutants that increase endosomal retention. In mutants that block endosomal entry, we also uncover an alternative, low-efficiency Notch trafficking route that can contribute to signaling. Our data show that endosomal access of the Notch receptor is critical to achieve physiological levels of signaling and further suggest that altered residence in distinct endocytic compartments could underlie pathologies involving aberrant Notch pathway activation.

scholarly journals Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling

2015 ◽  
Vol 210 (2) ◽  
pp. 303-318 ◽  
Author(s):  
Maria J. Gomez-Lamarca ◽  
Laura A. Snowdon ◽  
Ekatarina Seib ◽  
Thomas Klein ◽  
Sarah J. Bray
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Critical Role ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Dnaj Protein ◽  
Pathway Activation ◽  
Proliferation And Differentiation ◽  
Signal Activation

Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised. Strikingly, when the retromer component Vps26 was depleted at the same time, Notch no longer accumulated and instead was ectopically activated. Likewise, depletion of ESCRT-0 components Hrs or Stam in combination with Rme-8 also led to high levels of ectopic Notch activity. Together, these results highlight the importance of Rme-8 in coordinating normal endocytic recycling route and reveal that its absence predisposes toward conditions in which pathological Notch signaling can occur.

scholarly journals Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 521
Author(s):  
Catia Giovannini ◽  
Francesca Fornari ◽  
Fabio Piscaglia ◽  
Laura Gramantieri
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Hepatitis Virus ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Gamma Secretase ◽  
Stem Cell Maintenance ◽  
Pathway Activation ◽  
Promising Therapeutic Approach ◽  
Conserved Genes

The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles in hepatocellular carcinoma (HCC) affecting neoplastic growth, invasion capability and stem like properties. A specific knowledge of the deregulated expression of each Notch receptor and ligand, coupled with resultant phenotypic changes, is still lacking in HCC. Therefore, while interfering with Notch signaling might represent a promising therapeutic approach, the complexity of Notch/ligands interactions and the variable consequences of their modulations raises concerns when performed in undefined molecular background. The gamma-secretase inhibitors (GSIs), representing the most utilized approach for Notch inhibition in clinical trials, are characterized by important adverse effects due to the non-specific nature of GSIs themselves and to the lack of molecular criteria guiding patient selection. In this review, we briefly summarize the mechanisms involved in Notch pathway activation in HCC supporting the development of alternatives to the γ-secretase pan-inhibitor for HCC therapy.

scholarly journals Notch pathway activation targets AML-initiating cell homeostasis and differentiation

2013 ◽  
Vol 210 (2) ◽  
pp. 301-319 ◽  
Author(s):  
Camille Lobry ◽  
Panagiotis Ntziachristos ◽  
Delphine Ndiaye-Lobry ◽  
Philmo Oh ◽  
Luisa Cimmino ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Notch Signaling ◽  
Myeloproliferative Neoplasms ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Notch Receptor ◽  
Pathway Activation ◽  
Function Models

Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia.

scholarly journals Homodimerization of Erythropoietin Receptor by a Bivalent Monoclonal Antibody Triggers Cell Proliferation and Differentiation of Erythroid Precursors

Blood ◽  
1997 ◽  
Vol 89 (2) ◽  
pp. 473-482 ◽  
Author(s):  
Helmut Schneider ◽  
Warak Chaovapong ◽  
David J. Matthews ◽  
Cyrus Karkaria ◽  
Robert T. Cass ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mathematic Model ◽  
Receptor Activation ◽  
Erythropoietin Receptor ◽  
Fab Fragment ◽  
Erythroid Progenitor ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Erythroid Precursors ◽  
Dependent Cell

Abstract Erythropoietin (EPO) stimulates proliferation and differentiation of erythroid progenitor cells. Several lines of evidence indicate that the most likely mechanism of EPO receptor (EPO-R) activation by EPO is homodimerization of the receptor on the surface of erythrocyte precursors. Therefore, we argued that it should be possible to raise EPO-R monoclonal antibodies (MoAbs) that would activate the receptor by dimerization and thus mimic EPO action. We have identified such an agonist MoAb (MoAb34) directed against the extracellular EPO binding domain of the EPO-R. This bivalent IgG antibody triggers the proliferation of EPO-dependent cell lines and induces differentiation of erythroid precursors in vitro. In contrast, the monovalent Fab fragment, which cannot dimerize the receptor, is completely inactive. The mechanism of receptor activation by homodimerization implies that at high ligand concentrations the formation of 1:1 receptor/ligand complexes is favored over 2:1 complexes, thereby turning the ligand agonist into an antagonist. Thus, EPO and MoAb34 should self-antagonize at high concentrations in both cell proliferation and differentiation assays. Our data indeed demonstrate that EPO and MoAb34 antagonize ligand-dependent cell proliferation with IC50 values of approximately 20 and 2 μmol/L, respectively. Erythroid colony formation (BFUe) is inhibited at MoAb34 concentrations above 1 μmol/L. Furthermore, we analyzed the MoAb34:EPO-R interaction using a mathematic model describing antibody-mediated receptor dimerization. The data for proliferation and differentiation activity were consistent with the receptor dimer formation on the cell surface predicted by the model.

scholarly journals The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

PLoS Biology ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. e3001334
Author(s):  
Miren Maicas ◽  
Ángela Jimeno-Martín ◽  
Andrea Millán-Trejo ◽  
Mark J. Alkema ◽  
Nuria Flames
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Cell Signalling ◽  
Notch Pathway ◽  
Receptor Activation ◽  
Notch Signalling ◽  
Notch Receptor ◽  
Specific Gene ◽  
Effector Genes

During development, signal-regulated transcription factors (TFs) act as basal repressors and upon signalling through morphogens or cell-to-cell signalling shift to activators, mediating precise and transient responses. Conversely, at the final steps of neuron specification, terminal selector TFs directly initiate and maintain neuron-type specific gene expression through enduring functions as activators. C. elegans contains 3 types of serotonin synthesising neurons that share the expression of the serotonin biosynthesis pathway genes but not of other effector genes. Here, we find an unconventional role for LAG-1, the signal-regulated TF mediator of the Notch pathway, as terminal selector for the ADF serotonergic chemosensory neuron, but not for other serotonergic neuron types. Regulatory regions of ADF effector genes contain functional LAG-1 binding sites that mediate activation but not basal repression. lag-1 mutants show broad defects in ADF effector genes activation, and LAG-1 is required to maintain ADF cell fate and functions throughout life. Unexpectedly, contrary to reported basal repression state for LAG-1 prior to Notch receptor activation, gene expression activation in the ADF neuron by LAG-1 does not require Notch signalling, demonstrating a default activator state for LAG-1 independent of Notch. We hypothesise that the enduring activity of terminal selectors on target genes required uncoupling LAG-1 activating role from receiving the transient Notch signalling.

scholarly journals Structural basis of SUFU–GLI interaction in human Hedgehog signalling regulation

2013 ◽  
Vol 69 (12) ◽  
pp. 2563-2579 ◽  
Author(s):  
Amy L. Cherry ◽  
Csaba Finta ◽  
Mikael Karlström ◽  
Qianren Jin ◽  
Thomas Schwend ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Negative Regulator ◽  
Structural Basis ◽  
Hedgehog Signalling ◽  
Intrinsically Disordered ◽  
X Ray Scattering ◽  
Cell Proliferation And Differentiation ◽  
Pathway Activation ◽  
Proliferation And Differentiation ◽  
Disordered Loop

Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU–GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU–GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics.

scholarly journals Activation of Notch Signaling by Oocytes and Jag1 in Mouse Ovarian Granulosa Cells

Endocrinology ◽  
2019 ◽  
Vol 160 (12) ◽  
pp. 2863-2876 ◽  
Author(s):  
Nisan Hubbard ◽  
Rexxi D Prasasya ◽  
Kelly E Mayo
Keyword(s):  
Notch Signaling ◽  
Germ Cells ◽  
Granulosa Cells ◽  
Target Gene ◽  
Notch Pathway ◽  
Ovarian Granulosa Cells ◽  
Pathway Activation ◽  
Proliferation And Differentiation ◽  
Initial Activation ◽  
Notch Activation

Abstract The Notch pathway plays diverse and complex roles in cell signaling during development. In the mammalian ovary, Notch is important for the initial formation and growth of follicles, and for regulating the proliferation and differentiation of follicular granulosa cells during the periovulatory period. This study seeks to determine the contribution of female germ cells toward the initial activation and subsequent maintenance of Notch signaling within somatic granulosa cells of the ovary. To address this issue, transgenic Notch reporter (TNR) mice were crossed with Sohlh1-mCherry (S1CF) transgenic mice to visualize Notch-active cells (EGFP) and germ cells (mCherry) simultaneously in the neonatal ovary. To test the involvement of oocytes in activation of Notch signaling in ovarian somatic cells, we ablated germ cells using busulfan, a chemotherapeutic alkylating agent, or investigated KitWv/Wv (viable dominant white-spotting) mice that lack most germ cells. The data reveal that Notch pathway activation in granulosa cells is significantly suppressed when germ cells are reduced. We further demonstrate that disruption of the gene for the Notch ligand Jag1 in oocytes similarly impacts Notch activation and that recombinant JAG1 enhances Notch target gene expression in granulosa cells. These data are consistent with the hypothesis that germ cells provide a ligand, such as Jag1, that is necessary for activation of Notch signaling in the developing ovary.

scholarly journals Notch-Directed Germ Cell Proliferation Is Mediated by Proteoglycan-Dependent Transcription

2020 ◽  
Author(s):  
Sandeep Gopal ◽  
Aqilah Amran ◽  
Andre Elton ◽  
Leelee Ng ◽  
Roger Pocock
Keyword(s):  
Cell Proliferation ◽  
Germ Cell ◽  
Cell Fate ◽  
Notch Receptor ◽  
Cell Fate Decisions ◽  
Calcium Dependent ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Germline Proliferation ◽  
Membrane Bound

Notch receptors are essential membrane-bound regulators of cell proliferation and differentiation in metazoa. In the nematode Caenorhabditis elegans, correct expression of GLP-1 (germline proliferation-1), a germline-expressed Notch receptor, is important for germ cell maintenance. However, mechanisms that regulate GLP-1 expression are undefined. Here, we demonstrate that an AP-2 transcription factor (APTF-2) regulates GLP-1 expression through calcium-dependent binding to a conserved motif in the glp-1 promoter. Our data reveals that SDN-1 (syndecan-1), a transmembrane proteoglycan, regulates a TRP calcium channel in the soma to modulate the interaction between APTF-2 and glp-1 promoter - thus providing a potential communication nexus between the germline and its somatic environment to control germ cell fate decisions.

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