The roles of receptor and ligand endocytosis in regulating Notch signaling

Cell-cell signaling is a central process in the formation of multicellular organisms. Notch (N) is the receptor of a conserved signaling pathway that regulates numerous developmental decisions, and the misregulation of N has been linked to various physiological and developmental disorders. The endocytosis of N and its ligands is a key mechanism by which N-mediated cell-cell signaling is developmentally regulated. We review here the recent findings that have highlighted the importance and complexity of this regulation.

[1]  D. Birnbaum,et al.  Interaction between Two Ubiquitin-Protein Isopeptide Ligases of Different Classes, CBLC and AIP4/ITCH* , 2002, The Journal of Biological Chemistry.

[2]  R. J. Fleming,et al.  Structural conservation of Notch receptors and ligands. , 1998, Seminars in cell & developmental biology.

[3]  P. Rakic,et al.  Processing of the notch ligand delta by the metalloprotease Kuzbanian. , 1999, Science.

[4]  H. Krämer,et al.  Mutations in the Drosophila hook gene inhibit endocytosis of the boss transmembrane ligand into multivesicular bodies , 1996, The Journal of cell biology.

[5]  Erin Fitch,et al.  Fat facets and Liquid facets promote Delta endocytosis and Delta signaling in the signaling cells , 2004, Development.

[6]  Bing Zhang,et al.  A specific protein substrate for a deubiquitinating enzyme: Liquid facets is the substrate of Fat facets. , 2002, Genes & development.

[7]  Christel Brou,et al.  The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and γ-secretase , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  B. Wendland Epsins: adaptors in endocytosis? , 2002, Nature Reviews Molecular Cell Biology.

[9]  M. Cornell,et al.  The Drosophila melanogaster Suppressor of deltex gene, a regulator of the Notch receptor signaling pathway, is an E3 class ubiquitin ligase. , 1999, Genetics.

[10]  Y. Kanda,et al.  Binding of Delta1, Jagged1, and Jagged2 to Notch2 Rapidly Induces Cleavage, Nuclear Translocation, and Hyperphosphorylation of Notch2 , 2000, Molecular and Cellular Biology.

[11]  F. Schweisguth,et al.  Notch Signaling: Endocytosis Makes Delta Signal Better , 2003, Current Biology.

[12]  L. Szilágyi,et al.  Soluble Jagged‐1 is able to inhibit the function of its multivalent form to induce hematopoietic stem cell self‐renewal in a surrogate in vitro assay , 2004, Journal of leukocyte biology.

[13]  David G. Drubin,et al.  A Pathway for Association of Receptors, Adaptors, and Actin during Endocytic Internalization , 2003, Cell.

[14]  M. Gonzalez-Gaitan,et al.  The endocytic protein alpha-Adaptin is required for numb-mediated asymmetric cell division in Drosophila. , 2002, Developmental cell.

[15]  T. Hunter,et al.  Recognition and Ubiquitination of Notch by Itch, a Hect-type E3 Ubiquitin Ligase* , 2000, The Journal of Biological Chemistry.

[16]  H. Okano,et al.  Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis , 2001, International Journal of Developmental Neuroscience.

[17]  J. Hsieh,et al.  A secreted Delta1‐Fc fusion protein functions both as an activator and inhibitor of Notch1 signaling , 2002, Journal of neuroscience research.

[18]  Alexander M. van der Bliek,et al.  Dynamin-like protein encoded by the Drosophila shibire gene associated with vesicular traffic , 1991, Nature.

[19]  P. De Camilli,et al.  The association of epsin with ubiquitinated cargo along the endocytic pathway is negatively regulated by its interaction with clathrin. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  F. Schweisguth,et al.  Two Distinct E3 Ubiquitin Ligases Have Complementary Functions in the Regulation of Delta and Serrate Signaling in Drosophila , 2005, PLoS biology.

[21]  M. Cornell,et al.  Regulation of Notch Endosomal Sorting and Signaling by Drosophila Nedd4 Family Proteins , 2004, Current Biology.

[22]  P. Heitzler,et al.  Novel Notch alleles reveal a Deltex-dependent pathway repressing neural fate , 2001, Current Biology.

[23]  S. Artavanis-Tsakonas,et al.  Genetic characterization of the Drosophila melanogaster Suppressor of deltex gene: A regulator of notch signaling. , 1998, Genetics.

[24]  M. Cornell,et al.  Down-regulation of Notch target gene expression by Suppressor of deltex. , 2003, Developmental biology.

[25]  S. Hitchcock-DeGregori Actin assembly , 1980, Nature.

[26]  F. Turner,et al.  Relationships between complex Delta expression and the specification of retinal cell fates during Drosophila eye development , 1995, Mechanisms of Development.

[27]  S. Pasternak,et al.  The role of the endosomal/lysosomal system in amyloid-beta production and the pathophysiology of Alzheimer's disease: reexamining the spatial paradox from a lysosomal perspective. , 2003, Journal of Alzheimer's disease : JAD.

[28]  Y. Yarden,et al.  Molecular mechanisms underlying endocytosis and sorting of ErbB receptor tyrosine kinases , 2001, FEBS letters.

[29]  A L Cadavid,et al.  The function of the Drosophila fat facets deubiquitinating enzyme in limiting photoreceptor cell number is intimately associated with endocytosis. , 2000, Development.

[30]  Y. Jan,et al.  Control of Daughter Cell Fates during Asymmetric Division: Interaction of Numb and Notch , 1996, Neuron.

[31]  S. Artavanis-Tsakonas,et al.  Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. , 1995, Development.

[32]  F. Schweisguth,et al.  Unequal segregation of Neuralized biases Notch activation during asymmetric cell division. , 2003, Developmental cell.

[33]  Leonid Tarassishin,et al.  Processing of Notch and amyloid precursor protein by γ-secretase is spatially distinct , 2004 .

[34]  S. Artavanis-Tsakonas,et al.  Human deltex is a conserved regulator of Notch signalling , 1998, Nature Genetics.

[35]  P. Wong,et al.  Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. , 2004, The Journal of biological chemistry.

[36]  C. McGlade,et al.  Mammalian Numb Proteins Promote Notch1 Receptor Ubiquitination and Degradation of the Notch1 Intracellular Domain* , 2003, Journal of Biological Chemistry.

[37]  Hugo J Bellen,et al.  When cell biology meets development: endocytic regulation of signaling pathways. , 2002, Genes & development.

[38]  G. Struhl,et al.  Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch , 2004, Development.

[39]  M. W. Young,et al.  kuzbanian-mediated cleavage of Drosophila Notch. , 2002, Genes & development.

[40]  Leonid Tarassishin,et al.  Processing of Notch and amyloid precursor protein by gamma-secretase is spatially distinct. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[41]  G M Rubin,et al.  Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta. , 2001, Developmental cell.

[42]  N. Moschonas,et al.  neuralized Encodes a peripheral membrane protein involved in delta signaling and endocytosis. , 2001, Developmental cell.

[43]  T. Kiyota,et al.  The intracellular domain of X-Serrate-1 is cleaved and suppresses primary neurogenesis in Xenopus laevis , 2004, Mechanisms of Development.

[44]  Y. Jan,et al.  Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells , 1994, Cell.

[45]  Å. Engqvist-Goldstein,et al.  Actin assembly and endocytosis: from yeast to mammals. , 2003, Annual review of cell and developmental biology.

[46]  K. Matsuno,et al.  Drosophila Nedd4 Regulates Endocytosis of Notch and Suppresses Its Ligand-Independent Activation , 2004, Current Biology.

[47]  E. Lai Protein Degradation: Four E3s For The Notch Pathway , 2002, Current Biology.

[48]  A. Parks,et al.  Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. , 2000, Development.

[49]  Cheol‐Hee Kim,et al.  Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. , 2003, Developmental cell.

[50]  N. Baker,et al.  The roles of cis-inactivation by Notch ligands and of neuralized during eye and bristle patterning in Drosophila , 2004, BMC Developmental Biology.

[51]  Ning Chen,et al.  The lateral signal for LIN-12/Notch in C. elegans vulval development comprises redundant secreted and transmembrane DSL proteins. , 2004, Developmental cell.

[52]  Wenbiao Chen,et al.  Three modules of zebrafish Mind bomb work cooperatively to promote Delta ubiquitination and endocytosis. , 2004, Developmental biology.

[53]  D. Selkoe,et al.  The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. , 2003, The Journal of biological chemistry.

[54]  G. Boulianne,et al.  Neuralized functions as an E3 ubiquitin ligase during Drosophila development , 2001, Current Biology.

[55]  S. Sisodia,et al.  The Notch Ligands, Delta1 and Jagged2, Are Substrates for Presenilin-dependent “γ-Secretase” Cleavage* , 2003, The Journal of Biological Chemistry.

[56]  I. Bernstein,et al.  Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(-) cord blood cells. , 2002, The Journal of clinical investigation.

[57]  C. Poodry shibire, a neurogenic mutant of Drosophila. , 1990, Developmental biology.

[58]  Tokiharu Takahashi,et al.  Integrity of intracellular domain of Notch ligand is indispensable for cleavage required for release of the Notch2 intracellular domain , 2002, The EMBO journal.

[59]  S. Artavanis-Tsakonas,et al.  deltex, a locus interacting with the neurogenic genes, Notch, Delta and mastermind in Drosophila melanogaster. , 1990, Genetics.

[60]  K. Blumer,et al.  A WASp Homolog Powers Actin Polymerization-Dependent Motility of Endosomes In Vivo , 2003, Current Biology.

[61]  S. Artavanis-Tsakonas,et al.  Cytosolic interaction between deltex and Notch ankyrin repeats implicates deltex in the Notch signaling pathway. , 1994, Development.

[62]  C. Doe,et al.  Sanpodo and Notch act in opposition to Numb to distinguish sibling neuron fates in the Drosophila CNS. , 1998, Development.

[63]  H. Bellen,et al.  The Drosophila sanpodo gene controls sibling cell fate and encodes a tropomodulin homolog, an actin/tropomyosin-associated protein. , 1998, Development.

[64]  A. Israël,et al.  Monoubiquitination and endocytosis direct γ-secretase cleavage of activated Notch receptor , 2004, The Journal of cell biology.

[65]  E. Lai,et al.  Xenopus neuralized is a ubiquitin ligase that interacts with XDelta1 and regulates Notch signaling. , 2001, Developmental cell.

[66]  F. Schweisguth,et al.  Snail is required for Delta endocytosis and Notch-dependent activation of single-minded expression , 2003, Development Genes and Evolution.

[67]  M. Muskavitch,et al.  Complex proteolytic processing acts on Delta, a transmembrane ligand for Notch, during Drosophila development. , 1998, Molecular biology of the cell.

[68]  D. Selkoe,et al.  The Notch Ligands, Jagged and Delta, Are Sequentially Processed by α-Secretase and Presenilin/γ-Secretase and Release Signaling Fragments* , 2003, Journal of Biological Chemistry.

[69]  M. Kessels,et al.  The syndapin protein family: linking membrane trafficking with the cytoskeleton , 2004, Journal of Cell Science.

[70]  Jean Gruenberg,et al.  The biogenesis of multivesicular endosomes , 2004, Nature Reviews Molecular Cell Biology.

[71]  B. Trask,et al.  The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. , 1998, Immunity.

[72]  F. Maxfield,et al.  Endocytic recycling , 2004, Nature Reviews Molecular Cell Biology.

[73]  M. Itoh,et al.  Neurogenic phenotype of mind bomb mutants leads to severe patterning defects in the zebrafish hindbrain , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[74]  J. Skeath,et al.  Numb inhibits membrane localization of Sanpodo, a four-pass transmembrane protein, to promote asymmetric divisions in Drosophila. , 2003, Developmental cell.

[75]  S. Artavanis-Tsakonas,et al.  Secreted forms of DELTA and SERRATE define antagonists of Notch signaling in Drosophila. , 1997, Development.

[76]  P. Scambler,et al.  HIRA, a mammalian homologue of Saccharomyces cerevisiae transcriptional co-repressors, interacts with Pax3 , 1998, Nature Genetics.

[77]  L. Liaw,et al.  Soluble Jagged 1 Represses the Function of Its Transmembrane Form to Induce the Formation of the Src-dependent Chord-like Phenotype* , 2001, The Journal of Biological Chemistry.

[78]  B. Barres,et al.  Notch Receptor Activation Inhibits Oligodendrocyte Differentiation , 1998, Neuron.

[79]  P. Transidico,et al.  Clathrin-independent endocytosis of ubiquitinated cargos. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[80]  M. Vartiainen,et al.  The WASP-Arp2/3 pathway: genetic insights. , 2004, Current opinion in cell biology.

[81]  J. Aster,et al.  Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. , 2002, Immunity.

[82]  B. Wendland,et al.  Endocytosis of membrane receptors: two pathways are better than one. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[83]  T. Schedl,et al.  Epsin potentiates Notch pathway activity in Drosophila and C. elegans , 2004, Development.

[84]  Iva Greenwald,et al.  Endocytosis-mediated downregulation of LIN-12/Notch upon Ras activation in Caenorhabditis elegans , 2002, Nature.

[85]  P. Pelicci,et al.  Numb Is an Endocytic Protein , 2000, The Journal of cell biology.

[86]  Ian G. Mills,et al.  Curvature of clathrin-coated pits driven by epsin , 2002, Nature.

[87]  T. Schüpbach,et al.  D-cbl, a Negative Regulator of the Egfr Pathway, Is Required for Dorsoventral Patterning in Drosophila Oogenesis , 2000, Cell.

[88]  Christin E Bland,et al.  Notch-induced Proteolysis and Nuclear Localization of the Delta Ligand* , 2003, The Journal of Biological Chemistry.

[89]  I. Greenwald,et al.  Interchangeability of Caenorhabditis elegans DSL proteins and intrinsic signalling activity of their extracellular domains in vivo. , 1995, Development.

[90]  P. Wong,et al.  Association of γ-Secretase with Lipid Rafts in Post-Golgi and Endosome Membranes* , 2004, Journal of Biological Chemistry.

[91]  F. Schweisguth,et al.  Wasp, the Drosophila Wiskott-Aldrich Syndrome Gene Homologue, Is Required for Cell Fate Decisions Mediated by Notch Signaling , 2001, The Journal of cell biology.

[92]  R. Soldi,et al.  The Non-transmembrane Form of Delta1, but Not of Jagged1, Induces Normal Migratory Behavior Accompanied by Fibroblast Growth Factor Receptor 1-dependent Transformation* , 2004, Journal of Biological Chemistry.

[93]  H. Hirai,et al.  Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells. , 2003, Immunity.

[94]  S. Beyer,et al.  c-Cbl Binding and Ubiquitin-dependent Lysosomal Degradation of Membrane-associated Notch1* , 2002, The Journal of Biological Chemistry.

[95]  Richard B. Vallee,et al.  Multiple forms of dynamin are encoded by shibire, a Drosophila gene involved in endocytosis , 1991, Nature.

[96]  G. Rubin,et al.  The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta , 2005, Development.

[97]  Tian Xu,et al.  Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila , 1990, Cell.

[98]  Christel Brou,et al.  The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[99]  H. Okano,et al.  Drosophila Deltex mediates Suppressor of Hairless-independent and late-endosomal activation of Notch signaling , 2004, Development.

[100]  R. Fehon,et al.  Implications of dynamic patterns of Delta and Notch expression for cellular interactions during Drosophila development. , 1993, Development.

[101]  P. Rørth,et al.  Hrs mediates downregulation of multiple signalling receptors in Drosophila , 2003, EMBO reports.

[102]  Ricardo C T Aguiar,et al.  The BAL-binding Protein BBAP and Related Deltex Family Members Exhibit Ubiquitin-Protein Isopeptide Ligase Activity* , 2003, Journal of Biological Chemistry.

[103]  S. Aho Soluble form of Jagged1: Unique product of epithelial keratinocytes and a regulator of keratinocyte differentiation , 2004, Journal of cellular biochemistry.

[104]  C. Rieder,et al.  Greatwall kinase , 2004, The Journal of cell biology.

[105]  Raphael Kopan,et al.  Notch: a membrane-bound transcription factor. , 2002, Journal of cell science.

[106]  S. Artavanis-Tsakonas,et al.  The intracellular deletions of Delta and Serrate define dominant negative forms of the Drosophila Notch ligands. , 1996, Development.

[107]  G. Struhl,et al.  Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. , 2000, Molecular cell.

[108]  B. Shilo,et al.  Unidirectional Notch signaling depends on continuous cleavage of Delta , 2004, Development.

[109]  R. J. Fleming,et al.  A dominant-negative form of Serrate acts as a general antagonist of Notch activation. , 1997, Development.

[110]  P. P. Di Fiore,et al.  Distinct monoubiquitin signals in receptor endocytosis. , 2003, Trends in biochemical sciences.

[111]  J Kimble,et al.  lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans. , 1994, Development.

[112]  P. Simpson,et al.  Requirement for dynamin during Notch signaling in Drosophila neurogenesis. , 1997, Developmental biology.

[113]  S. Artavanis-Tsakonas,et al.  Down-regulation of Delta by proteolytic processing , 2002, The Journal of cell biology.

[114]  I. Bernstein,et al.  Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling. , 2000, Journal of cell science.

[115]  R. Ueda,et al.  Regulation of Notch signaling by Drosophila heparan sulfate 3-O sulfotransferase , 2004, The Journal of cell biology.

[116]  Eric C. Lai,et al.  Notch signaling: control of cell communication and cell fate , 2004, Development.

[117]  Joseph L Goldstein,et al.  Regulated Intramembrane Proteolysis A Control Mechanism Conserved from Bacteria to Humans , 2000, Cell.

[118]  S. Artavanis-Tsakonas,et al.  A member of the Notch group of interacting loci, deltex encodes a cytoplasmic basic protein. , 1994, Genetics.