Chapter Fourteen - Biodiversity and Noncanonical Notch Signaling

https://doi.org/10.1016/S0070-2153(10)92014-0Get rights and content

Abstract

Early genetics in flies revealed that Notch is a complex pleiotropic locus. We now know that Notch is a receptor that plays prominent roles during development and functions locally in many tissues to instruct cell fate decisions. Drosophila has been an excellent model to identify genetically the elements that contribute to the canonical Notch signaling transduction machinery defined as DSL–Notch–CSL–MAML axis. This core pathway is required in many biological events in all animals. Though the canonical Notch pathway is relatively simple, and as the steps of the events are now more deeply understood, an increasing number of reports in the last decade show that many other molecules can influence Notch signaling, some by competing with a given element of the cascade. This may occur at any step bringing more diversity and plasticity to the Notch pathway. Most of these regulatory molecules act in a context-specific manner and/or are themselves key regulators in other pathways, providing increasing examples of how connections among distinct pathway modulate each other (“cross talk”). The noncanonical signals discussed in this chapter are broadly defined and correspond to the following: DSL-independent activations, interactions with non-DSL ligands, CSL-independent signaling, signal transduction without cleavage, differential posttranslational modifications, competition/protection for a cofactor, and cross talk with other signaling pathways [Wnt, bone morphogenic protein (BMP), NF-κB, etc.]. Though some deemed controversial, these events may impact human diseases. Understanding the molecular nature of these events will allow avoidance of adverse effects during possible clinical treatments. In this review, we will focus on some noncanonical Notch activities and their in vivo significance during developmental and pathological processes.

Section snippets

A Wide Range of Notch-dependent Activities

Notch receptors trigger a wide range of cell fate choices through intercellular communications. Notch signaling is conserved across metazoan species and besides acquisition of specific cell fates and potentials enables also diverse cellular responses, like differentiation, proliferation, or apoptosis. Notch receptors function in multiple tissues and is used at various stages of development (Artavanis-Tsakonas et al., 1999, Kopan and Ilagan, 2009, Lai, 2004). Drosophila, where only a single

Noncanonical Notch Signaling and Bristle Patterning

In recent years, increasing examples of biological events have been reported that do not require the classical Delta-like DSL ligands nor the Su(H)-like CSL mediator. Some data reveal such a different pathway acting during Drosophila neurogenesis where multiple connections with the Wg signaling exist (Ramain et al., 2001, Hayward et al., 2008). The thorax of the flies exhibits two types of sensory organs, few large bristles, or macrochaetae, and numerous small bristles, or microchaetae. The

Noncanonical N Signals in Vertebrates

Increasing number of noncanonical Notch signals were observed and explored in mammals. In general, we define these as situations where signal transduction is possible independent of at least one component of the Notch core. These events include alternative ligands, alternative mediators, or proteolysis-independent Notch signals.

Misappropriation by Viruses

Some pathological virus infections can alienate CSL factors from their canonical function to serve the viruses’ own advantages. Viruses like the Epstein–Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and adenovirus type 5 proteins are known to release multiple proteins necessary for cellular transformation that bind CSL and may modulate CSL-dependent transcription (Hsieh and Hayward, 1995). For example, the KSHV RTA factor and the EBV EBNA2 have antagonist consequence on B

New Insights on MAML

Recently, a noncanonical function of mam has been studied that enhances Hedgehog signaling specifically in stem cells of the Drosophila ovary (Vied and Kalderon, 2009). Rather than being a coactivator of Notch in these tissues, mam functions in follicle stem cells independently of Notch. There are increasing examples where mam-like transcriptional factors play unexpected roles in other signaling pathways including muscle differentiation and myopathies (MEF2C), tumor suppressor pathway (p53),

Rheostat and Fine-tuning

Nemo-like kinases (NLK) represent a family of conserved protein kinases that function in various tissues and biological events. Though Drosophila nemo was suspected to be involved in Notch signaling (Verheyen et al., 1996, Kankel et al., 2007), a very recent study in zebra fish established the NICD of Notch1 as a target and its phosphorylation contributes to decrease the formation of the CSL–MAML–NICD transcriptional complex (Ishitani et al., 2010). Knockdown Nlk leads to activation of HES

Nonnuclear Mechanisms

Finally, few reports described Notch signal transduction events that are independent from the cleavage.

Discussion

Notch mutants and most of the receptor transduction machinery were first identified in Drosophila. Due to partial redundancy among the Notch genes in vertebrates, the study of Notch receptors remains more sophisticated in Mouse or other mammalian models. Drosophila has only one receptor, and its powerful genetics continues to allow the identification of new modifiers that influence Notch signaling (Mummery-Widmer et al., 2009). Though the functional aspects of the different Notch domains has

Acknowledgments

I apologize to colleagues whose work was not cited. I am grateful to Inna Biryukova for artworks. This work was supported by the Association pour la Recherche sur le Cancer (ARC), the CNRS, the INSERM and the University of Strasbourg.

References (116)

  • M.V. Gustafsson et al.

    Hypoxia requires Notch signaling to maintain the undifferentiated cell state

    Dev. Cell

    (2005)
  • P. Heitzler et al.

    The choice of cell fate in the epidermis of Drosophila

    Cell

    (1991)
  • Q.D. Hu et al.

    F3/Contactin acts as a functional ligand for Notch during oligodendrocyte maturation

    Cell

    (2003)
  • S. Koelzer et al.

    Regulation of expression of Vg and establishment of the dorsoventral compartment boundary in the wing imaginal disc by Suppressor of Hairless

    Dev. Biol.

    (2006)
  • R. Kopan et al.

    The canonical Notch signaling pathway: unfolding the activation mechanism

    Cell

    (2009)
  • M. Le Gall et al.

    Molecular separation of two signaling pathways for the receptor. Notch

    Dev. Biol.

    (2008)
  • T. Minamizato et al.

    CCN3/NOV inhibits BMP-2-induced osteoblast differentiation by interacting with BMP and Notch signaling pathways

    Biochem. Biophys. Res. Commun.

    (2007)
  • A. Miyamoto et al.

    Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation

    J. Biol. Chem.

    (2006)
  • Y. Nam et al.

    Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes

    Cell

    (2006)
  • Y. Pan et al.

    γ-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis.

    Dev. Cell

    (2004)
  • L. Poellinger et al.

    Modulating Notch signaling by pathway-intrinsic and pathway-extrinsic mechanisms

    Curr. Opin. Genet. Dev.

    (2008)
  • P. Ramain et al.

    Novel Notch alleles reveal a Deltex-dependent pathway repressing neural fate

    Curr. Biol.

    (2001)
  • I. Rebay et al.

    Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor

    Cell

    (1993)
  • J.C. Rusconi et al.

    Evidence for a novel Notch pathway required for muscle precursor selection in Drosophila

    Mech. Dev.

    (1998)
  • K. Sakamoto et al.

    The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway

    J. Biol. Chem.

    (2002)
  • I. Aifantis et al.

    Notch, NF-kBs and the making of T cell leukemia

    Cell Cycle

    (2007)
  • A.R. Albig et al.

    Microfibril-associate glycoprotein-2 (MAGP-2) promotes angiogenic cell sprouting by blocking Notch signaling in endothelial cells

    Microvasc. Res.

    (2008)
  • E.J. Allenspach et al.

    Notch signaling in cancer

    Cancer Biol. Therapy

    (2002)
  • V. Ambros

    Cell cycle-dependent sequencing of cell fate decisions in Caenorhabditis elegans vulva precursor cells

    Development

    (1999)
  • S. Artavanis-Tsakonas et al.

    Notch signaling: cell fate control and signal integration in development

    Science

    (1999)
  • J.C. Aster et al.

    Notch signaling in leukemia

    Annu. Rev. Pathol.

    (2008)
  • J.D. Axelrod et al.

    Interaction between Wingless and Notch signaling pathways mediated by dishevelled

    Science

    (1996)
  • S. Ayyar et al.

    NF-kB/Rel-mediated regulation of the neural fate in Drosophila

    PloS ONE

    (2007)
  • B. Bedogni et al.

    Notch1 is an effector of Akt and hypoxia in melanoma development

    J. Clin. Invest.

    (2008)
  • T.M. Beres et al.

    PTF1 is an organ-specific and Notch-independent basic helix-loop-helix complex containing the mammalian Suppressor of Hairless (RBP-J) or its paralogue, RBP-L

    Mol. Cell. Biol.

    (2006)
  • A. Blokzijl et al.

    Cross-talk between the Notch and the TGF-β signaling pathways mediated by interaction of the Notch intracellular domain with Smad3

    J. Cell Biol.

    (2003)
  • S.J. Bray

    Notch signalling: a simple pathway becomes complex

    Nat. Rev. Mol. Cell Biol.

    (2006)
  • Y. Chen et al.

    Oxygen concentration determines the biological effects of Notch-1 signaling in adenocarcinoma of the lung

    Cancer Res.

    (2007)
  • M.Y. Chiang et al.

    Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1

    Mol. Cell. Biol.

    (2006)
  • C. Cras-Méneur et al.

    Presenilins, Notch dose control the fate of pancreatic endocrine progenitors during a narrow developmental window

    Genes Dev.

    (2009)
  • C. Dahlqvist et al.

    Functional Notch signaling is required for BMP4-induced inhibition of myogenic differentiation

    Development

    (2003)
  • R.M. Demarest et al.

    It’s T-ALL about Notch

    Oncogene

    (2008)
  • S. Demehri et al.

    Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity

    PLoS Biol.

    (2008)
  • R.J. Diederich et al.

    Cytosolic interaction between deltex and Notch ankyrin repeats implicated deltex in the Notch signalling pathway

    Development

    (1994)
  • B. D’Souza et al.

    The many facets of Notch ligands

    Oncogene

    (2008)
  • S. Eliasz et al.

    Notch1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway

    Oncogene

    (2010)
  • U.M. Fiuza et al.

    Mechanisms of ligand-mediated inhibition in Notch signaling activity in Drosophila

    Dev. Dyn.

    (2010)
  • C.J. Fryer et al.

    Mastermind mediates chromatin-specific transcription and turnover enhancer complex

    Genes Dev.

    (2002)
  • A.J. Giraldez et al.

    Wingless and Notch signaling provide cell survival cues and control cell proliferation during wing development

    Development

    (2003)
  • C. Grabher et al.

    Notch1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia

    Nat. Rev. Cancer

    (2006)
  • Cited by (0)

    View full text