The multifaceted role of Notch in cancer (original) (raw)
Related papers
Notch Signaling in Development and Cancer
Endocrine Reviews, 2007
Notch is an evolutionarily conserved local cell signaling mechanism that participates in a variety of cellular processes: cell fate specification, differentiation, proliferation, apoptosis, adhesion, epithelial-mesenchymal transition, migration, and angiogenesis. These processes can be subverted in Notch-mediated pathological situations. In the first part of this review, we will discuss the role of Notch in vertebrate central nervous system development, somitogenesis, cardiovascular and endocrine development, with attention to the mechanisms by which Notch regulates cell fate specification and patterning in these tissues. In the second part, we will review the molecular aspects of Notch-mediated neoplasias, where Notch can act as an oncogene or as a tumor suppressor. From all these studies, it becomes evident that the outcome of Notch signaling is strictly contextdependent and differences in the strength, timing, cell type, and context of the signal may affect the final outcome. It is essential to understand how Notch integrates inputs from other signaling pathways and how specificity is achieved, because this knowledge may be relevant for future therapeutic applications. (Endocrine Reviews 28: 339-363, 2007) I. Introduction: Elements of the Notch Signaling Pathway II. Notch in Vertebrate CNS Development A. Notch promotes progenitor diversification and inhibits neuronal differentiation B. Notch in gliogenesis III. Notch in Somitogenesis IV. Notch in Cardiovascular Development and Homeostasis V. Notch in Endocrine Development: Pancreas, Gut, and Bone Endocrine Cells A. Pancreatic development B. Gut development C. Bone development VI. Notch in Cancer A. Notch in hematological tumors B. Notch as an oncogene in solid tumors: breast and gut cancer C. Differential roles of NOTCH in two types of skin cancer: keratinocyte-derived carcinoma and melanomas D. Notch in EMT and tumor progression VII. Concluding Remarks I. Introduction: Elements of the Notch Signaling Pathway N OTCH IS ONE of the fundamental signaling pathways that regulate metazoan development and adult tissue homeostasis. The Notch mutant was initially described in Drosophila, based on its dominant wing-notching phenotype (1). The study of the embryonic lethal phenotype caused by complete lack of Notch function (2) and its complex allelic series and genetic interactions (3) brought Notch to the forefront, so that in the mid-1980s the Drosophila Notch gene product was identified (4, 5). Notch is a local signaling mechanism that is evolutionarily conserved throughout the animal kingdom. Mammals have four Notch proteins (Notch 1-4; Refs. 6-10 and Fig. 1A) that are membrane-bound type I receptors (with a single-pass transmembrane domain), harboring a large extracellular domain involved in ligand binding, and a cytoplasmatic domain involved in signal transduction. The extracellular domain contains a variable number of epidermal growth factor (EGF)-like repeats that are critical for binding interactions (11, 12). The EGF-like repeats are followed by three cysteinerich LIN12/Notch repeats (LNR) that prevent signaling in the absence of the ligand. The Notch intracellular domain (NICD) contains a RAM23 domain (13), six ankyrin/cdc10 repeats involved in protein-protein interactions (14), two nuclear localization signals (N1 and N2), a transcriptional activation domain (TAD) that differs among the four receptors, and a PEST sequence [rich in proline (P), glutamic acid (E), serine (S) and threonine (T)] that negatively regulates protein stability (15). The Notch receptors are synthesized as single precursor proteins that are cleaved by a furin-convertase activity (16) at site 1 or S1 (Fig. 1B) during transport to the cell surface, where they are expressed as heterodimers (17). The mammalian Notch ligands Delta1 (18), Delta3 (19), Delta4 (20), Jagged1 (21), and Jagged2 (22) are named after the Drosophila homologs Delta and Serrate, respectively, and are also membrane-bound. They have an amino-terminal domain termed DSL (for Delta, Serrate and LAG-2 domain), followed by a variable number of EGF-like repeats. In addition, Jagged1 and Jagged2 harbor a cysteine-rich domain (CR; Fig. 1A). Notch signaling is regulated by posttranslational modification events, such as glycosylation, and by other modifications involving the extracellular domains of both receptors and ligands, such as the extension of sugar residues by the
Journal of Biological Chemistry, 2011
The Notch signal transduction pathway mediates important cellular functions through direct cell-to-cell contact. Deregulation of Notch activity can lead to an altered cell proliferation and has been linked to many human cancers. Casein kinase 2 (CK2), a ubiquitous kinase, regulates several cellular processes by phosphorylating proteins involved in signal transduction, gene expression, and protein synthesis. In this report we identify Notch ICD as a novel target of phosphorylation by CK2. Using mapping and mutational studies, we identified serine 1901, located in the ankyrin domain of Notch, as the target amino acid. Interestingly, phosphorylation of serine 1901 by CK2 appears to generate a second phosphorylation site at threonine 1898. Furthermore, threonine 1898 phosphorylation only occurs when Notch forms a complex with Mastermind and CSL. Phosphorylation of both threonine 1898 and serine 1901 resulted in decreased binding of the Notch-Mastermind-CSL ternary complex to DNA and consequently lower transcriptional activity. These data indicate that the phosphorylation of serine 1901 and threonine 1898 negatively regulates Notch function by dissociating the complex from DNA. This study identifies a new component involved in regulation of Notch ICD transcriptional activity, reinforcing the notion that a precise and tight regulation is required for this essential signaling pathway. Notch signaling regulates several cellular processes such as cell proliferation, differentiation and apoptosis, thereby playing a key role in cellular homeostasis. There are four Notch family members that show complementary and combinatorial expression patterns depending on cell type (1, 2). Notch signaling is initiated by the interaction between the DSL ligand (Delta, Serrate, and Lag-2) and the extracellular domain of Notch, which is brought about by cell-to-cell contact. This interaction leads to proteolytic cleavage events that result in the release of Notch intracellular domain (Notch ICD) from the plasma membrane,
The Role of Intracellular Trafficking of Notch Receptors in Ligand-Independent Notch Activation
Biomolecules, 2021
Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting.
Journal of Biological Chemistry, 2008
The Notch pathway regulates the development of many tissues and cell types and is involved in a variety of human diseases, making it an attractive potential therapeutic target. This promise has been limited by the absence of potent inhibitors or agonists that are specific for individual human Notch receptors (NOTCH1-4). Using an unbiased functional screening, we identified monoclonal antibodies that specifically inhibit or induce activating proteolytic cleavages in NOTCH3. Remarkably, the most potent inhibitory and activating antibodies bind to overlapping epitopes within a juxtamembrane negative regulatory region that protects NOTCH3 from proteolysis and activation in its resting autoinhibited state. The inhibitory antibodies revert phenotypes conveyed on 293T cells by NOTCH3 signaling, such as increased cellular proliferation, survival, and motility, whereas the activating antibody mimics some of the effects of ligand-induced Notch activation. These findings provide insights into the mechanisms of Notch autoinhibition and activation and pave the way for the further development of specific antibody-based modulators of the Notch receptors, which are likely to be of utility in a wide range of experimental and therapeutic settings.
Proteolytic Cleavage of Notch: “HIT and RUN”
Current Molecular Medicine, 2011
The Notch pathway is a highly conserved signaling pathway in multicellular eukaryotes essential in controlling spatial patterning, morphogenesis and homeostasis in embryonic and adult tissues. Notch proteins coordinate cell-cell communication through receptor-ligand interactions between adjacent cells. Notch signaling is frequently deregulated by oncogenic mutation or overexpression in many cancer types. Notch activity is controlled by three sequential cleavage steps leading to ectodomain shedding and transcriptional activation. Here we review the key regulatory steps in the activation of Notch, from receptor maturation to receptor activation (HIT) via a rate-limiting proteolytic cascade (RUN) in the context of species-specific differences.