Trends in Cell Biology
ReviewNon-canonical Notch signaling: emerging role and mechanism
Section snippets
Canonical versus non-canonical Notch signaling
Nearly a century ago, the name Notch was given to an allele found to cause notched fly wings; since this time, the gene encoding the transmembrane protein Notch has been extensively investigated for its function and mechanisms 1, 2, 3, 4. The investigation led to the identification of key members of Notch signaling including ligands, proteases and transcriptional co-factors, forming the dogma of the canonical Notch signal transduction pathway (Box 1). Although Notch mediates a number of
Early evidence of non-canonical Notch function
Some of the earliest evidence for non-canonical Notch signaling came from in vitro studies, in which increased Notch1 levels inhibited the differentiation of myoblast (C2C12) cells into muscle cells 8, 9, 10. The authors reported that, unlike conventional Notch signaling, the inhibition of myoblast differentiation did not require the CSL interacting domain of Notch1 and was not mediated by CSL or known Notch target genes, suggesting the existence of a CSL-independent Notch pathway 9, 10. In vivo
Functional interaction of non-canonical Notch and Wnt/β-catenin signaling
Notch exhibits recurrent crosstalk with Wnt/β-catenin signaling in numerous cell types and contexts during development (summarized in Table 1 in [34]). The interaction of Notch and Wnt signaling was first uncovered in the Drosophila wing imaginal disc, where Notch is co-expressed with Wingless (Drosophila Wnt-1) and enforces Wingless signaling 29, 35. Notch interacts with Wnt/β-catenin signaling in synergic or antagonistic ways, depending on the context 24, 27. The synergistic interactions
Molecular link between non-canonical Notch and Wnt signals: active β-catenin
Cleaved NICD has long been thought to be the activated form of Notch, whereas uncleaved membrane-bound Notch is thought to be biologically inactive and constantly internalized for recycling or degradation through an endo-lysosomal pathway [46]. Interestingly, uncleaved full-length Notch1 in the plasma membrane, generated by inactivating the Notch-processing protease Furin or site-specific mutagenesis of Furin target sequence in Notch, potently inhibits myogenesis of C2C12 myoblasts [8], which
Potential role of Numb in Notch and β-catenin regulation
While Notch had been defined as a fundamental mediator of extrinsic factors for cell-fate specification, Numb was identified as the primary intrinsic factor that antagonized Notch in classic studies in Drosophila [68]. This interaction depends on the spatio-temporal distribution of Numb during cell division to one pole of the cell resulting in asymmetric cell division in which daughter cells retained distinct properties and different fates 69, 70.
Numb might inhibit canonical Notch activity by
Physiological significance
During the past decade increasing evidence has suggested that a complex functional relation exists between Notch and Wnt signaling, particularly during establishment of stem and progenitor cell fate determination and cancer formation. The recent findings of how membrane-bound Notch post-translationally regulates Wnt/β-catenin signaling provide novel insight into this complex relation during fundamental biological and disease processes, such as proliferation, differentiation, lineage decisions
Concluding remarks
It has been puzzling that endogenous Notch protein is mostly detected at the cell membrane and/or cytoplasm but rarely seen in the nucleus. With accumulating evidence it is now becoming apparent that Notch can function in non-nuclear environments, where it affects canonical Wnt signaling by titrating active β-catenin levels. Although active β-catenin has emerged as a conserved mediator of a ligand/CSL-independent Notch pathway across species, it is probable that Notch interacts with additional
Acknowledgments
We thank P. Cheng, D. Srivastava, and Kwon lab members for helpful discussions. This work was supported by grants from NHLBI/NIH and AHA.
References (85)
Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats
Cell
(1985)The theory of the gene
Am. Nat.
(1917)The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch
Nature
(1988)Effect of Notch deficiencies
Dros. Inf. Serv.
(1939)Notch post-translationally regulates beta-catenin protein in stem and progenitor cells
Nat. Cell Biol.
(2011)Identification and characterization of presenilin-independent Notch signaling
J. Biol. Chem.
(2002)Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity
PLoS Biol.
(2008)Ligand-induced signaling in the absence of furin processing of Notch1
Dev. Biol.
(2001)Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts
Development
(1999)Notch signaling inhibits muscle cell differentiation through a CBF1-independent pathway
Development
(1996)
Notch inhibition of E47 supports the existence of a novel signaling pathway
Mol. Cell. Biol.
Mammalian NOTCH-1 activates beta1 integrins via the small GTPase R-Ras
J. Biol. Chem.
Bimodal functions of Notch-mediated signaling are involved in neural crest formation during avian ectoderm development
Development
Deltex/Dtx mediates NOTCH signaling in regulation of Bmp4 expression in cranial neural crest formation during avian development
Dev. Growth Differ.
Notch destabilises maternal beta-catenin and restricts dorsal-anterior development in Xenopus
Development
Modulation of the ligand-independent traffic of Notch by Axin and Apc contributes to the activation of Armadillo in Drosophila
Development
Ligand-independent traffic of Notch buffers activated Armadillo in Drosophila
PLoS Biol.
Repression by Notch is required before Wingless signalling during muscle progenitor cell development in Drosophila
Curr. Biol.
Evidence for a novel Notch pathway required for muscle precursor selection in Drosophila
Mech. Dev.
A widespread and early requirement for a novel Notch function during Drosophila embryogenesis
Dev. Biol.
Interaction between Notch and Hif-alpha in development and survival of Drosophila blood cells
Science
A role of receptor Notch in ligand cis-inhibition in Drosophila
Curr. Biol.
An activity of Notch regulates JNK signalling and affects dorsal closure in Drosophila
Curr. Biol.
Notch signaling targets the Wingless responsiveness of a Ubx visceral mesoderm enhancer in Drosophila
Curr. Biol.
Novel Notch alleles reveal a Deltex-dependent pathway repressing neural fate
Curr. Biol.
The abruptex mutations of notch disrupt the establishment of proneural clusters in Drosophila
Dev. Biol.
Wingless modulates the effects of dominant negative notch molecules in the developing wing of Drosophila
Dev. Biol.
Notch1 augments NF-kappaB activity by facilitating its nuclear retention
EMBO J.
Modulation of wingless signaling by Notch in Drosophila
Mech. Dev.
Notch modulates Wnt signalling by associating with Armadillo/beta-catenin and regulating its transcriptional activity
Development
Activated notch inhibits myogenic activity of the MADS-Box transcription factor myocyte enhancer factor 2C
Mol. Cell. Biol.
The notch intracellular domain can function as a coactivator for LEF-1
Mol. Cell. Biol.
Notch signaling: cell fate control and signal integration in development
Science
Wnt/Notch signalling and information processing during development
Development
Notch is required for wingless signaling in the epidermis of Drosophila
Cell
Convergence of Notch and beta-catenin signaling induces arterial fate in vascular progenitors
J. Cell Biol.
Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine
Proc. Natl. Acad. Sci. U.S.A.
Mesodermal cell fate decisions in Drosophila are under the control of the lineage genes numb, Notch, and sanpodo
Mech. Dev.
A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate
Nat. Cell Biol.
Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors
Proc. Natl. Acad. Sci. U.S.A.
Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation
EMBO J.
Notch tumor suppressor function
Oncogene
Cited by (183)
Insight into the role of multiple signaling pathways in regulating cancer stem cells of gynecologic cancers
2022, Seminars in Cancer BiologyNotch signaling in cancer: Complexity and challenges on the path to clinical translation
2022, Seminars in Cancer BiologyAGEs-induced MMP-9 activation mediated by Notch1 signaling is involved in impaired wound healing in diabetic rats
2022, Diabetes Research and Clinical PracticeCitation Excerpt :Upon binding of the Notch ligand to Notch receptors, the intracellular domain of Notch1 (NICD), which is the active form of Notch1, is released and translocated to the nucleus [20]. Recent studies demonstrated that Notch could non-canonically exert biological functions by cross-talk and signaling [21]. Specifically, Notch1 has been observed to active NF-κB promoter, and downregulation of Notch1 reduces NF-κB DNA-binding activity and concomitantly inhibits the expression and activation of MMP-9 in articular cartilage homeostasis and developmental events in Drosophila [22,23].
Targeting Pathways and Integrated Approaches to Treat Rheumatoid Arthritis
2024, Critical Reviews in Therapeutic Drug Carrier Systems
- *
These authors contributed equally to this work.