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Clinical Cancer Research Vol. 12, 1074-1079, February 2006
© 2006 American Association for Cancer Research

Molecular Pathways

Notch Signaling

Lucio Miele

Author's Affiliation: Department of Pathology, Pharmacology and Breast Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois

Requests for reprints: Lucio Miele, Breast Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Room 236, Building 112, 2160 South 1st Avenue, Maywood, IL 60153. Phone: 708-327-3298; Fax: 708-327-2245; E-mail: lmiele{at}lumc.edu.


   Background
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 Background
Recent Developments
 Notch Inhibitors as Cancer...
 References
 
The basics of Notch signaling. Notch ligands and receptors are type I membrane proteins that regulate cell fate during cell-cell contact (1, 2). Humans have four Notch receptors and five ligands: Delta-like-1, Delta-like-3, and Delta-like-4 and Jagged-1 and Jagged-2 (3). Notch receptors are heterodimeric proteins that are synthesized as single-chain precursors and cleaved into an extracellular (NEC) and a transmembrane (NTM) subunit by a furin-like protease in the trans-Golgi (1–3). Notch NEC subunits include a variable number of epidermal growth factor–like repeats and three Lin/Notch repeats (1, 2). These mediate the Ca2+-dependent interaction between NEC and NTM. NTM includes a transmembrane region followed by a "RAM23" sequence, a series of ankyrin repeats, a nuclear localization sequence, a polyglutamine stretch, and a PEST sequence, which modulates receptor half-life (1, 2). The RAM23 sequence and the ankyrin repeats interact with CSL transcription factors (mammalian CBF-1/Drosophila Suppressor of Hairless/Caenorhabditis elegans Lag-1; refs. 4, 5).

NEC glycosylation by Fringe glycosyltransferases regulates the relative affinity for ligands (1–3). Ligand binding dissociates NEC from NTM, and the NEC-ligand complex is trans-endocytosed into ligand-expressing cells (6). NEC dissociation triggers an extracellular cleavage in NTM by ADAM10 (a disintegrin and metalloprotease 10) or ADAM17 (1–3) followed by an intramembranous cleavage by {gamma}-secretase, a multisubunit membrane aspartyl protease that includes a catalytic subunit (Presenilin-1 or Presenilin-2), Pen-2, Aph1, and Nicastrin (7). This releases an intracellular domain (NIC) that translocates into the nucleus, where it modulates transcription via CSL factors (1–3).

All four mammalian Notches seem to use the same basic signaling pathway via CSL transcription factors (8), and specific pathways of individual homologues remain elusive. The mammalian CSL, CBF-1/RBP-J{kappa}, binds the sequence CGTGGGAA and acts as a constitutive repressor by recruiting a corepressor complex, including SMRT or N-coR, SKIP, CIR, and class I or II histone deacetylases (9), as well as SHARP (10), CtBP/CtIP (11), and, in Xenopus, methylated DNA-binding protein MeCP2 (12). Notch binding to CSL replaces the SMRT corepressor complex with a coactivator complex including SKIP, MAML1 (Mastermind in Drosophila), and histone acetyltransferases PCAF, GCN5, or p300 (1–3, 9), activating transcription of target genes. These include "Enhancer of Split" bHLH transcription factors in Drosophila and their mammalian homologues HES (1), HERP (13), and HEY (14) families, which modulate differentiation by regulating other bHLH proteins. HES1 also dimerizes with and activates signal transducers and activators of transcription 3 (15). Other Notch targets include p21Cip/Waf (16), cyclin D1 (17), cyclin A (18), transcription factors of the nuclear factor-{kappa}B (19), and poly(ADP-ribose) polymerase families (20, 21) and ubiquitin ligase SKP2, through which Notch triggers degradation of p27kip1 (22). The set of directly and indirectly Notch-regulated genes and proteins is probably very large and context dependent.

Phosphorylation of NIC by GSK-3ß (23), CDK8 (24), and possibly other kinases regulates its half-life. Several E3 ligases, including Sel-10 (25), Itch (26), c-Cbl (27), and Deltex (28) ubiquitinate Notch, triggering its degradation. Sel-10 catalyzes phosphorylation-dependent ubiquitination of nuclear NIC (25, 29).

Notch and cancer. Notch activation is oncogenic in many instances. NIC forms of all four Notch homologues act as oncogenes in vitro (30) and in animal models (31–34). EBV immortalizing protein EBNA-2, which is necessary for EBV-induced transformation, mimics Notch by activating CBF-1 (35, 36). Expression of Notch-1 NIC in mouse hematopoietic precursors causes T-cell leukemia/lymphomas (31). Notch-1 (34, 37) and Notch-4 (38) NIC cause mammary tumors in mice.

NEC deletions of Notch-1 were discovered in T-cell acute lymphoblastic leukemia (T-ALL; ref. 39). Subsequently, Weng et al. (40) discovered that activating mutations of Notch-1 are present in ~50% of T-ALL, making Notch-1 the most commonly activated oncogene in this disease. These mutations affect either the "heterodimerization domain" between the NEC and NTM subunits, facilitating NEC dissociation, or the COOH-terminal PEST region, increasing the half-life of NIC. Some T-ALL cases contain double-mutant Notch alleles.

Deregulated expression of Notch receptors, ligands, and targets is observed in solid tumors, including cervical, head and neck, endometrial, renal, lung, pancreatic, ovarian, breast and prostate carcinomas, osteosarcoma, mesothelioma, gliomas, and medulloblastomas (41–55). High-level expression of Notch-1 and Jagged-1 is associated with poor prognosis in breast cancer (56) and with metastasis in prostate cancer (55). Hodgkin's lymphomas, anaplastic large-cell non-Hodgkin's lymphomas, some acute myeloid leukemias, B-cell chronic lymphoid leukemias, and multiple myeloma also show deregulated expression of Notch receptors or ligands (57–60). Ras oncogenes activate wild-type Notch signaling, and Notch activation is required for Ras-mediated transformation of human fibroblasts (50). Transforming growth factor-{alpha} activates Notch through Ras in pancreatic carcinogenesis (41). Given the incidence of Ras mutations and Ras-activating mutations in human cancers, it is perhaps not surprising that aberrant Notch activation is observed in numerous malignancies.

The molecular basis for the oncogenic activity of Notch NICs remains unclear. Notch NIC transforms several cell types when expressed with oncoproteins that disable the G1-S checkpoint, such as adenovirus E1A (30), human papillomavirus E6 and E7 (61, 62), Ras (63), Myc (64), or SV40 large T (49). Notch may contribute to tumorigenesis by inhibiting differentiation, promoting survival or accelerating proliferation. Potentially oncogenic targets of Notch-1 include cyclins D1 and D3 (17, 34, 65), cyclin A (18), SKP2 (22), phosphatidylinositol 3-kinase (61, 66), AKT (61), ERBB2 (67), nuclear factor-{kappa}B (68), and nuclear factor-{kappa}B2 (69), ß-catenin (70), signal transducers and activators of transcription-3 (15), and hypoxia-inducible factor-1{alpha} (71).

An important exception is the epidermis, where Notch-1 acts as a tumor suppressor. Notch signaling induces growth arrest and differentiation in human (21) and murine (16) keratinocytes in vitro. Tissue-specific ablation of Notch-1 in murine epidermis causes hyperplasia, corneal epithelial proliferation, and, eventually, spontaneous basal cell carcinoma–like tumors and facilitates chemical-induced carcinogenesis (72). In primary keratinocytes, Notch-1 induces p21cip1/waf1 via CBF-1 (16) and via HES-1–mediated inhibition of calcipressin, resulting in calcineurin activation (73). The reasons for the differential behavior of Notch in keratinocytes as opposed to other cell types are still unclear. Lathion et al., however, showed that expression of Notch-1 NIC at moderate levels transforms keratinocytes with human papillomavirus oncoproteins, whereas high-level overexpression inhibits growth (62). Like p53, Notch-1 may activate different targets when expressed at low or high levels. Keratinocytes may have an optimum level of Notch-1 for p21 differentiation and survival. High levels of Notch-1 would lead to growth arrest via p21cip1/waf1. Moderate levels would support survival without blocking proliferation and synergize with other oncogenes. The clinical implications of these observations in humans are still unclear but deserve careful consideration. Notch inhibitors, which are in early clinical development, will have to be carefully monitored for potential dermatologic adverse effects, and strategies to circumvent such effects may have to be devised.


   Recent Developments
Top
 Background
 Recent Developments
Notch Inhibitors as Cancer...
 References
 
Several recent observations have highlighted the importance of ubiquitin ligases and endocytic sorting in regulating Notch signaling. In Drosophila, ubiquitination of Delta and Serrate by E3 ligases Neuralized or Mindbomb is necessary for Epsin-mediated endocytosis (74) and Notch activation (75, 76). Monoubiquitination at a juxta membrane Lys1749 (in Notch-1) and endocytosis of Notch are suggested to be required for {gamma}-secretase cleavage (77). This seems to contradict data indicating that {gamma}-secretase exists as an active complex with Notch at the membrane (78). There is evidence that Presenilin-1 can act as an intracellular scaffold (79) and is associated with newly synthesized Notch (80). Presenilin-1, with Nicastrin (81, 82), may form a scaffold for Notch during its maturation, be present at the membrane with Notch, and then cleave it after ligand binding and endocytosis. Three recent articles support this model: endosomal accumulation of Drosophila Notch caused by mutations in endosomal sorting regulators Vps25 or Erupted enhances Notch activity and cell proliferation (83–85). Endocytosis can also inhibit Notch signaling: negative regulator Numb causes Notch endocytosis with {alpha}-adaptin (86, 87) followed by proteasome-mediated Notch degradation (88). Thus, depending on cellular context, Notch may be sorted via endocytosis either to an activation pathway or to a degradation pathway (Fig. 1).


Figure 1
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  		Fig. 1. Simplified diagram of a current model of canonical Notch signaling. Notch receptors exist in the membrane as heterodimers associated with {gamma}-secretase. Notch ligands bind the Notch NEC subunit and, after ubiquitination (UQ) by Neuralized or Mindbomb, dissociate it from NTM and trans-endocytose it via Epsin adaptor. This causes ADAM10 or ADAM17 to clip the extracellular portion of NTM, generating a cleavage intermediate. This is monoubiquitinated near the membrane by an E3 ligase (possibly Deltex), triggering endocytosis and {gamma}-secretase cleavage, which releases NIC. When endocytosis is mediated by Numb and {alpha}-adaptin, it leads to Notch degradation instead. Ubiquitination of Notch by Deltex in the presence of Kurz also leads to degradation. Cleaved NIC enters the nucleus, where it causes the dissociation of the SMRT corepressor complex from CSL, and recruits the MAML1 coactivator complex, resulting in transcription of target genes. Abbreviations: SMRT, silencing mediator of retinoid and thyroid hormones; CIR, CBF-1 interacting corepressor; SHARP, SMRT/HDAC-1–associated repressor protein; CtBP, COOH-terminal domain binding protein; CtIP, CtBP-interacting protein; HDAC, histone deacetylase; HAT, histone acetyltransferase (P/CAF, GCN5, or p300); MAML1, Mastermind-like 1; SKIP, ski-interacting protein.

 
Noncanonical Notch signaling is attracting increasing attention. There is evidence that ligands other than Delta/Jagged, such as F3/contactin (89), can activate Notch. Binding to non-CSL transcription factors, such as Nur77 (39), ß-catenin (70), or hypoxia-inducible factor-1{alpha} (71), may mediate a still underappreciated subset of Notch effects. Some CSL-independent effects may be mediated by RING-finger E3 ligase Deltex (90–92). Deltex is transcriptionally up-regulated by Notch, binds Notch, and may be both a mediator and an inhibitor of Notch signaling (93). Deltex inhibits Notch (34, 94), and recent data indicate that ß-arrestin Kurz forms a ternary complex with Notch and Deltex, leading to Notch ubiquitination and degradation (28). Deltex also catalyzes the ubiquitination and degradation of MEKK1 (95), mediating cross-talk between Notch and mitogen-activated protein kinase pathways. Deltex may have different effects on Notch depending on other binding partners. Finally, there is evidence that Notch-1 NIC has protein kinase scaffold and anti-scaffold functions: Sade et al. (66) reported that NIC forms a complex with p56Lck in T cells, promoting the phosphorylation of phosphatidylinositol 3-kinase by p56Lck, thus activating the phosphatidylinositol 3-kinase/AKT pathway. Conversely, Notch inhibits c-Jun NH2-terminal kinase activation by associating with scaffold JNP1 (96).

In terms of tumor biology, although much attention has gone to the role of Notch in cancer cells, recent data suggest that Notch signaling is also important in tumor microenvironment. Inside-out signaling by Notch ligands from tumor cells activating Notch in stromal cells can promote tumorigenesis. Myeloma cells overexpress Jagged-2, activating Notch in stromal cells and inducing expression of myeloma growth factor interleukin-6 (97). Head and neck squamous cell carcinomas overexpress Jagged-1, which activates Notch in endothelial cells, promoting angiogenesis (98). Finally, an area of active investigation is the role of Notch signaling in cancer stem cells. Evidence suggests that many cancers, especially leukemias, breast cancers, and gliomas, contain a rare population of cells that are highly tumorigenic, unlike the bulk of cancer cells that are unable to form tumors in vivo. Even established cancer cell lines seem to contain this subpopulation. This has led to a theory that cancers arise from the transformation of normal tissue stem cells or poorly differentiated progenitor cells. Once transformed, these generate all other dead-end cancer cells through an aberrant process of tissue differentiation. The slowly proliferating cancer stem cells have indefinite self-replication ability and are highly resistant to chemotherapy (99, 100). According to this theory, conventional chemotherapy kills the majority of progeny, nontumorigenic cancer cells, but largely spares cancer stem cells, which accumulate mutations and eventually give rise to recurrences and metastases. Thus, novel therapeutic strategies that target pathways necessary to cell fate decisions in cancer stem cells should improve therapeutic outcomes. Normal stem cells from many tissues, including mammary epithelial stem cells (101), depend on Notch signaling for fate determination (102–105). Cancer stem cells isolated as dye-excluding side population from numerous cancer cell lines express high levels of Notch-1 (106). Very recent data indicate that stem-like cells contained in ductal carcinoma in situ clinical specimens have the same phenotype (107). Consequently, Notch signaling is considered one of the most attractive candidate targets in cancer stem cells.


   Notch Inhibitors as Cancer Therapeutics
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 Background
 Recent Developments
 Notch Inhibitors as Cancer...
References
 
Numerous studies have proposed inhibition of Notch signaling as a strategy for cancer treatment (2). Selective strategies include antisense, monoclonal antibodies, and RNA interference. Nonselective strategies include soluble or cell-associated Notch decoys, {gamma}-secretase inhibitors, intracellular MAML1 decoys, and Ras signaling inhibitors.

{gamma}-Secretase inhibitors (GSI) have the most immediate therapeutic potential. GSI cbz-IL-CHO has Notch-1–dependent antineoplastic activity in Ras-transformed fibroblasts (50). GSI z-Leu-leu-Nle-CHO induces apoptosis in melanoma cell lines and melanoma xenografts, but not normal melanocytes, via p53-independent up-regulation of NOXA (108). GSI compound E causes growth arrest in T-ALL cells (40). Like other small-molecule agents, GSIs have multiple effects. {gamma}-Secretase cleaves all Notch receptors and some ligands but also ErbB4, syndecan, CD44, and other proteins (2, 7). Therapeutically, this may actually be advantageous because many cancers coexpress two or three different Notch homologues. Some GSIs may also affect proteases other than {gamma}-secretase. Pharmacologic studies with GSIs need to carefully address target specificity, and a complementary transcriptional silencing approach is necessary in each model. Accumulating preclinical evidence has led to the opening of phase 1 trials of a GSI in T-ALL and breast cancer. The pathways affected by Notch inhibition are likely to be context dependent, and rational combinations of GSIs with other antineoplastic drugs will require mechanistic studies in individual models. Looking beyond GSIs, ADAM inhibitors may find clinical uses to inhibit the first ligand-induced Notch cleavage. In light of recent evidence, blocking specific E3 ligases responsible for ubiquitination of Notch ligands or monoubiquitination of Notch receptors may be an alternate approach.

Small molecules that interfere with Notch coactivator binding may selectively inhibit CSL signaling but not noncanonical signaling. Depending on the relative importance of Notch downstream pathways in individual cancers and normal tissues, this may be an advantage or a disadvantage compared with drugs that block receptor activation. If intracellularly acting Notch inhibitors are shown to have unacceptable off-target effects, biologics, such as decoys and monoclonal antibodies to ligands or receptors, may be preferable. An important question is whether selective inhibition of one of the four Notch homologues may be therapeutically desirable. In this case, monoclonal antibodies would be the agent of choice, and the best candidate may be Notch-4, given its more limited tissue distribution in normal mammals. Finally, it will be important to establish whether cancer stem cell–targeted agents are optimally active alone or in rational combinations (e.g., a Notch inhibitor with a Hedgehog inhibitor). Accumulating knowledge about cross-talk between target pathways will guide therapeutic choices.

The potential toxicities of cancer stem cell–targeted therapies are largely unexplored. Random mutagenesis caused by DNA damage is unlikely for most such agents, but effects on normal tissue stem cells are obviously possible. In general, it may be preferable to use these agents in pulsed, high-dose regimens rather than in chronic regimens that could eventually alter the differentiation of essential stem cells in the epidermis, intestine, or other vital tissues.

It is obviously far too early to evaluate the prospects of these drugs. It is fair to say, however, that Notch inhibition in cancer deserves a very thorough investigation because it could simultaneously affect many of the most attractive therapeutic targets recently identified, including signal transducers, and activators of transcription 3, nuclear factor-{kappa}B, AKT, cyclins, NOXA, and others.


   Acknowledgments
 
I thank Lynda Song, Paola Rizzo, and Clodia Osipo for critical reading and apologize for omitting many primary references due to space limitations.


   Footnotes
 
Grant support: National Cancer Institute grant RO1 CA 84065.

Received 11/22/05; revised 12/16/05; accepted 12/16/05.


   References
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 Background
 Recent Developments
 Notch Inhibitors as Cancer...
 References
 

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