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Home , Cell fate determination, Ligand (biochemistry), Notch 4, NUMB (gene)

Molecular Pathways

Notch Signaling Lucio Miele

Background MeCP2 (12). Notch binding to CSL replaces the SMRT complex with a coactivator complex including The basics of Notch signaling. Notch and receptors SKIP, MAML1 (Mastermind in ), and histone are type I membrane that regulate cell fate during acetyltransferases PCAF, GCN5, or p300 (1–3, 9), activating cell-cell contact (1, 2). Humans have four Notch receptors transcription of target . These include ‘‘Enhancer of Split’’ and five ligands: Delta-like-1, Delta-like-3, and Delta-like-4 bHLH transcription factors in Drosophila and their mammalian and Jagged-1 and Jagged-2 (3). Notch receptors are hetero- homologues HES (1), HERP (13), and HEY (14) families, dimeric proteins that are synthesized as single-chain pre- which modulate differentiation by regulating other bHLH cursors and cleaved into an extracellular (NEC) and a proteins. HES1 also dimerizes with and activates signal trans- transmembrane (NTM) subunit by a furin-like protease in ducers and activators of transcription 3 (15). Other Notch the trans-Golgi (1–3). Notch NEC subunits include a variable targets include p21Cip/Waf (16), cyclin D1 (17), cyclin A (18), n number of epidermal –like repeats and three transcription factors of the nuclear factor- B (19), and Lin/Notch repeats (1, 2). These mediate the Ca2+-dependent poly(ADP-) polymerase families (20, 21) and interaction between NEC and NTM.NTM includes a transmem- ligase SKP2, through which Notch triggers degradation of brane region followed by a ‘‘RAM23’’ sequence, a series of p27kip1 (22). The set of directly and indirectly Notch-regulated ankyrin repeats, a nuclear localization sequence, a polyglut- genes and proteins is probably very large and context amine stretch, and a PEST sequence, which modulates dependent. IC half-life (1, 2). The RAM23 sequence and the ankyrin Phosphorylation of N by GSK-3h (23), CDK8 (24), and repeats interact with CSL transcription factors (mammalian possibly other kinases regulates its half-life. Several E3 ligases, CBF-1/Drosophila Suppressor of Hairless/ including Sel-10 (25), Itch (26), c-Cbl (27), and Deltex (28) Lag-1; refs. 4, 5). ubiquitinate Notch, triggering its degradation. Sel-10 catalyzes IC NEC glycosylation by Fringe glycosyltransferases regulates the phosphorylation-dependent ubiquitination of nuclear N relative affinity for ligands (1–3). binding dissociates (25, 29). NEC from NTM, and the NEC-ligand complex is trans- Notch and cancer. Notch activation is oncogenic in many IC endocytosed into ligand-expressing cells (6). NEC instances. N forms of all four Notch homologues act as triggers an extracellular in NTM by ADAM10 in vitro (30) and in animal models (31–34). EBV (a disintegrin and metalloprotease 10) or ADAM17 (1–3) immortalizing protein EBNA-2, which is necessary for EBV- followed by an intramembranous cleavage by g-secretase, induced transformation, mimics Notch by activating CBF-1 a multisubunit membrane aspartyl protease that includes (35, 36). Expression of Notch-1 NIC in mouse hematopoietic a catalytic subunit (Presenilin-1 or Presenilin-2), Pen-2, Aph1, precursors causes T-cell leukemia/lymphomas (31). Notch-1 and Nicastrin (7). This releases an intracellular domain (NIC) (34, 37) and Notch-4 (38) NIC cause mammary tumors in that translocates into the nucleus, where it modulates mice. transcription via CSL factors (1–3). NEC deletions of Notch-1 were discovered in T-cell acute All four mammalian Notches seem to use the same basic lymphoblastic leukemia (T-ALL; ref. 39). Subsequently, Weng signaling pathway via CSL transcription factors (8), and specific et al. (40) discovered that activating mutations of Notch-1 are pathways of individual homologues remain elusive. The present in f50% of T-ALL, making Notch-1 the most mammalian CSL, CBF-1/RBP-Jn, binds the sequence CGTGG- commonly activated in this disease. These mutations GAA and acts as a constitutive repressor by recruiting affect either the ‘‘heterodimerization domain’’ between the NEC a corepressor complex, including SMRT or N-coR, SKIP, CIR, and NTM subunits, facilitating NEC dissociation, or the COOH- and class I or II histone deacetylases (9), as well as SHARP (10), terminal PEST region, increasing the half-life of NIC. Some CtBP/CtIP (11), and, in Xenopus, methylated DNA-binding 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, glio- Author’s Affiliation: Department of Pathology, and Breast mas, and medulloblastomas (41–55). High-level expression of Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois Notch-1 and Jagged-1 is associated with poor prognosis in Received 11/22/05; revised 12/16/05; accepted 12/16/05. breast cancer (56) and with metastasis in prostate cancer (55). Grant support: National Cancer Institute grant RO1CA 84065. Hodgkin’s lymphomas, anaplastic large-cell non-Hodgkin’s Requests for reprints: Lucio Miele, Breast Cancer Program, Cardinal Bernardin lymphomas, some acute myeloid leukemias, B-cell chronic Cancer Center, Loyola University Chicago, Room 236, Building 112, 2160 South lymphoid leukemias, and multiple myeloma also show deregu- 1st Avenue, Maywood, IL 60153. Phone: 708-327-3298; Fax: 708-327-2245; E-mail: [email protected]. lated expression of Notch receptors or ligands (57–60). Ras F 2006 American Association for Cancer Research. oncogenes activate wild-type Notch signaling, and Notch doi:10.1158/1078-0432.CCR-05-2570 activation is required for Ras-mediated transformation of

Clin Cancer Res 2006;12(4) February 15, 2006 1074 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2006 American Association for Cancer Research. Notch Signaling human fibroblasts (50). Transforming growth factor-a activates its maturation, be present at the membrane with Notch, and Notch through Ras in pancreatic carcinogenesis (41). Given the then cleave it after ligand binding and endocytosis. Three incidence of Ras mutations and Ras-activating mutations in recent articles support this model: endosomal accumulation of human cancers, it is perhaps not surprising that aberrant Notch Drosophila Notch caused by mutations in endosomal sorting activation is observed in numerous malignancies. regulators Vps25 or Erupted enhances Notch activity and cell The molecular basis for the oncogenic activity of Notch NICs proliferation (83–85). Endocytosis can also inhibit Notch remains unclear. Notch NIC transforms several cell types when signaling: negative regulator Numb causes Notch endocytosis expressed with oncoproteins that disable the G1-S checkpoint, with a-adaptin (86, 87) followed by -mediated such as adenovirus E1A (30), human papillomavirus E6 and E7 Notch degradation (88). Thus, depending on cellular context, (61, 62), Ras (63), (64), or SV40 large T (49). Notch may Notch may be sorted via endocytosis either to an activation contribute to tumorigenesis by inhibiting differentiation, pathway or to a degradation pathway (Fig. 1). promoting survival or accelerating proliferation. Potentially Noncanonical Notch signaling is attracting increasing atten- oncogenic targets of Notch-1 include cyclins D1 and D3 (17, 34, tion. There is evidence that ligands other than Delta/Jagged, 65), cyclin A (18), SKP2 (22), phosphatidylinositol 3-kinase such as F3/contactin (89), can activate Notch. Binding to non- (61, 66), AKT (61), ERBB2 (67), nuclear factor-nB (68), and CSL transcription factors, such as Nur77 (39), h-catenin (70), nuclear factor-nB2 (69), h-catenin (70), signal transducers or hypoxia-inducible factor-1a (71), may mediate a still and activators of transcription-3 (15), and hypoxia-inducible underappreciated subset of Notch effects. Some CSL- factor-1a (71). independent effects may be mediated by RING-finger E3 ligase An important exception is the epidermis, where Notch-1 acts Deltex (90–92). Deltex is transcriptionally up-regulated by as a tumor suppressor. Notch signaling induces growth arrest Notch, binds Notch, and may be both a mediator and an and differentiation in human (21) and murine (16) keratino- inhibitor of Notch signaling (93). Deltex inhibits Notch cytes in vitro. Tissue-specific ablation of Notch-1 in murine (34, 94), and recent data indicate that h-arrestin Kurz forms a epidermis causes hyperplasia, corneal epithelial proliferation, ternary complex with Notch and Deltex, leading to Notch and, eventually, spontaneous basal cell carcinoma–like ubiquitination and degradation (28). Deltex also catalyzes the tumors and facilitates chemical-induced carcinogenesis ubiquitination and degradation of MEKK1 (95), mediating (72). In primary keratinocytes, Notch-1 induces p21cip1/waf1 cross-talk between Notch and mitogen-activated via CBF-1 (16) and via HES-1–mediated inhibition of pathways. Deltex may have different effects on Notch depend- calcipressin, resulting in calcineurin activation (73). The ing on other binding partners. Finally, there is evidence that reasons for the differential behavior of Notch in keratinocytes Notch-1 NIC has protein kinase scaffold and anti-scaffold as opposed to other cell types are still unclear. Lathion et al., functions: Sade et al. (66) reported that NIC forms a complex however, showed that expression of Notch-1 NIC at moderate with p56Lck in T cells, promoting the phosphorylation of levels transforms keratinocytes with human papillomavirus phosphatidylinositol 3-kinase by p56Lck, thus activating the oncoproteins, whereas high-level overexpression inhibits phosphatidylinositol 3-kinase/AKT pathway. Conversely, growth (62). Like , Notch-1 may activate different targets Notch inhibits c-Jun NH2-terminal kinase activation by when expressed at low or high levels. Keratinocytes may have associating with scaffold JNP1 (96). an optimum level of Notch-1 for differentiation and In terms of tumor , although much attention has survival. High levels of Notch-1 would lead to growth arrest gone to the role of Notch in cancer cells, recent data suggest via p21cip1/waf1. Moderate levels would support survival that Notch signaling is also important in tumor microenviron- without blocking proliferation and synergize with other ment. Inside-out signaling by Notch ligands from tumor cells oncogenes. The clinical implications of these observations in activating Notch in stromal cells can promote tumorigenesis. humans are still unclear but deserve careful consideration. Myeloma cells overexpress Jagged-2, activating Notch in Notch inhibitors, which are in early clinical development, will stromal cells and inducing expression of myeloma growth have to be carefully monitored for potential dermatologic factor interleukin-6 (97). Head and neck squamous cell adverse effects, and strategies to circumvent such effects may carcinomas overexpress Jagged-1, which activates Notch in have to be devised. endothelial cells, promoting (98). Finally, an area of active investigation is the role of Notch signaling in cancer Recent Developments stem cells. Evidence suggests that many cancers, especially leukemias, breast cancers, and gliomas, contain a rare Several recent observations have highlighted the importance population of cells that are highly tumorigenic, unlike the of ubiquitin ligases and endocytic sorting in regulating Notch bulk of cancer cells that are unable to form tumors in vivo. Even signaling. In Drosophila, ubiquitination of Delta and Serrate by established cancer cell lines seem to contain this subpopula- E3 ligases Neuralized or Mindbomb is necessary for Epsin- tion. This has led to a theory that cancers arise from the mediated endocytosis (74) and Notch activation (75, 76). transformation of normal tissue stem cells or poorly differen- Monoubiquitination at a juxta membrane Lys1749 (in Notch- tiated progenitor cells. Once transformed, these generate all 1) and endocytosis of Notch are suggested to be required for other dead-end cancer cells through an aberrant process of g-secretase cleavage (77). This seems to contradict data tissue differentiation. The slowly proliferating cancer stem cells indicating that g-secretase exists as an active complex with have indefinite self-replication ability and are highly resistant to Notch at the membrane (78). There is evidence that (99, 100). According to this theory, conven- Presenilin-1 can act as an intracellular scaffold (79) and is tional chemotherapy kills the majority of progeny, nontumori- associated with newly synthesized Notch (80). Presenilin-1, genic cancer cells, but largely spares cancer stem cells, which with Nicastrin (81, 82), may form a scaffold for Notch during accumulate mutations and eventually give rise to recurrences

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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 g-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 orADAM17to 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 g-secretase cleavage, which releases NIC.When endocytosis is mediated by Numb and a-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 SMRTcorepressor complex from CSL, and recruits the MAML1coactivator complex, resulting in transcription of target genes. Abbreviations: SMRT, silencing mediator of and thyroid ; CIR, CBF-1interacting 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. and metastases. Thus, novel therapeutic strategies that target the same (107). Consequently, Notch signaling is pathways necessary to cell fate decisions in cancer stem cells considered one of the most attractive candidate targets in cancer should improve therapeutic outcomes. Normal stem cells from stem cells. many tissues, including mammary epithelial stem cells (101), depend on Notch signaling for fate determination (102–105). Notch Inhibitors as CancerTherapeutics Cancer stem cells isolated as dye-excluding side population from numerous cancer cell lines express high levels of Numerous studies have proposed inhibition of Notch Notch-1 (106). Very recent data indicate that stem-like cells signaling as a strategy for cancer treatment (2). Selective contained in ductal carcinoma in situ clinical specimens have strategies include antisense, monoclonal , and RNA

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interference. Nonselective strategies include soluble or cell- with that block receptor activation. If intracellularly associated Notch decoys, g-secretase inhibitors, intracellular acting Notch inhibitors are shown to have unacceptable off- MAML1 decoys, and Ras signaling inhibitors. target effects, biologics, such as decoys and monoclonal g-Secretase inhibitors (GSI) have the most immediate antibodies to ligands or receptors, may be preferable. An therapeutic potential. GSI cbz-IL-CHO has Notch-1–depen- important question is whether selective inhibition of one of the dent antineoplastic activity in Ras-transformed fibroblasts four Notch homologues may be therapeutically desirable. In (50). GSI z-Leu-leu-Nle-CHO induces in melanoma this case, monoclonal antibodies would be the agent of choice, cell lines and melanoma xenografts, but not normal melano- and the best candidate may be Notch-4, given its more limited cytes, via p53-independent up-regulation of NOXA (108). GSI tissue distribution in normal mammals. Finally, it will be compound E causes growth arrest in T-ALL cells (40). Like important to establish whether cancer stem cell–targeted agents other small-molecule agents, GSIs have multiple effects. are optimally active alone or in rational combinations (e.g., a g-Secretase cleaves all Notch receptors and some ligands but Notch inhibitor with a Hedgehog inhibitor). Accumulating also ErbB4, syndecan, CD44, and other proteins (2, 7). knowledge about cross-talk between target pathways will guide Therapeutically, this may actually be advantageous because therapeutic choices. many cancers coexpress two or three different Notch The potential of cancer stem cell–targeted therapies homologues. Some GSIs may also affect proteases other than are largely unexplored. Random mutagenesis caused by DNA g-secretase. Pharmacologic studies with GSIs need to carefully damage is unlikely for most such agents, but effects on normal address target specificity, and a complementary transcriptional tissue stem cells are obviously possible. In general, it may be silencing approach is necessary in each model. Accumulating preferable to use these agents in pulsed, high-dose regimens preclinical evidence has led to the opening of phase 1 trials of rather than in chronic regimens that could eventually alter the a GSI in T-ALL and breast cancer. The pathways affected by differentiation of essential stem cells in the epidermis, intestine, Notch inhibition are likely to be context dependent, and or other vital tissues. rational combinations of GSIs with other antineoplastic drugs It is obviously far too early to evaluate the prospects of these will require mechanistic studies in individual models. Looking drugs. It is fair to say, however, that Notch inhibition in cancer beyond GSIs, ADAM inhibitors may find clinical uses to deserves a very thorough investigation because it could inhibit the first ligand-induced Notch cleavage. In light of simultaneously affect many of the most attractive therapeutic recent evidence, blocking specific E3 ligases responsible for targets recently identified, including signal transducers, and ubiquitination of Notch ligands or monoubiquitination of activators of transcription 3, nuclear factor-nB, AKT, cyclins, Notch receptors may be an alternate approach. NOXA, and others. Small molecules that interfere with Notch coactivator binding may selectively inhibit CSL signaling but not non- Acknowledgments canonical signaling. Depending on the relative importance of Notch downstream pathways in individual cancers and normal I thank Lynda Song, Paola Rizzo, and Clodia Osipo for critical reading and apolo- tissues, this may be an advantage or a disadvantage compared gize for omitting many primary references due to space limitations.

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