Notch Receptors and Ligands: Signaling Pathway & Therapeutic Targets

The Notch signaling pathway plays a pivotal role in biological systems, regulating not only embryonic development and adult tissue homeostasis but also exerting dual functions in the initiation and progression of multiple cancers - acting as either a tumor suppressor or a driver of cancer cell proliferation, angiogenesis, and immune evasion. This dedicated resource systematically summarizes core knowledge on Notch1 - 4 receptors and DLL/JAG ligands, enabling you to rapidly identify high-quality recombinant proteins, antibodies, and ELISA kits to advance your research in oncology and other Notch-related disease areas.

Overview of the Notch Signaling Pathway

The Notch signaling pathway is an evolutionarily conserved cell-to-cell communication system, first identified through the "notched" wing phenotype in Drosophila. In mammals, it consists of four transmembrane receptors (Notch1–4) and five canonical ligands (DLL1, DLL3, DLL4, JAG1, JAG2), activated exclusively upon direct contact between adjacent cells to precisely regulate cell fate determination, differentiation, proliferation, and tissue homeostasis.

All Notch receptors are type I transmembrane proteins. They are cleaved by furin in the Golgi apparatus and trafficked to the cell membrane as heterodimers. Ligands are also transmembrane proteins expressed on the surface of neighboring cells. Upon ligand-receptor binding, two sequential proteolytic cleavages occur: an S2 cleavage mediated by ADAM metalloproteases, followed by an S3 cleavage catalyzed by γ-secretase. This releases the Notch intracellular domain (NICD), which translocates to the nucleus, forms a transcriptional complex with RBP-J and other co-factors, and activates target genes such as Hes and Hey, thereby transmitting the signal.

Figure: NOTCH Signaling Pathway ^[1]

(A. Ligand structural features; B. Receptor structural features; C. Signal reception and transduction process.)

Although the core mechanism is highly conserved, distinct Notch receptors and ligands exhibit significant differences in tissue distribution, binding preferences, and biological functions—for example, DLL4–Notch1 dominates angiogenesis, JAG1–Notch2 participates in kidney development, and DLL3 is aberrantly overexpressed in small cell lung cancer (SCLC). These specificities underscore the importance of precise target selection and reagent matching in research.

Characteristics of Notch Receptors and Ligands

The functional diversity of the Notch signaling pathway arises from the differential expression of its receptors and ligands across tissues and developmental stages, leading to context-dependent signaling outputs. The tables below summarize the expression profiles, core biological functions, and disease associations of the four Notch receptors and five canonical ligands for quick reference.

● Notch Receptor Family (Notch1 - 4)

Target	Primary Expression Sites	Core Biological Functions	Disease Associations
Notch1	Thymic T cells, vascular endothelium, neural progenitors, mammary epithelium	T-cell development, angiogenesis, stem cell maintenance	T-cell acute lymphoblastic leukemia (T-ALL) ^[2,3], breast cancer ^[4], melanoma ^[5], hepatocellular carcinoma ^[6], colorectal cancer ^[7], Alzheimer’s disease ^[20]
Notch2	Renal tubular epithelium, intrahepatic bile duct cells, B cells, bone marrow stroma	Kidney/bile duct development, B-cell differentiation, liver regeneration	Chronic lymphocytic leukemia (B-CLL) ^[8], small cell lung cancer ^[9], pancreatic cancer ^[10], breast cancer ^[11], Hajdu-Cheney syndrome ^[18], Alagille syndrome ^[19]
Notch3	Vascular smooth muscle cells, cerebral arterioles, pericytes	Vascular smooth muscle homeostasis, neurovascular function	Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) ^[12]
Notch4	Vascular endothelium, mammary epithelium	Mammary epithelial development, endothelial barrier function	Systemic sclerosis ^[13], melanoma ^[14], hepatocellular carcinoma ^[15], asthma ^[16], bipolar disorder ^[17]

● Notch Ligand Family (DLL/JAG)

Target	Primary Expression Sites	Core Biological Functions	Disease Associations
DLL1	Neural stem cells, somites, hematopoietic niche, intestinal crypts	Neurogenesis, somitogenesis, hematopoietic stem/progenitor cell regulation	Breast cancer ^[21], neuroblastoma ^[22], multiple myeloma ^[22]
DLL3	Neuroendocrine tissues, fetal brain, small cell lung cancer (SCLC)	Inhibits canonical Notch signaling; regulates neuroendocrine fate	Small cell lung cancer (SCLC) ^[24–26], neuroendocrine carcinomas ^[27]
DLL4	Vascular "tip cells", tumor-associated endothelium, thymic epithelium	Regulates angiogenic sprouting; restricts excessive tip cell formation	Colorectal cancer ^[28], breast cancer ^[29], lung cancer ^[30], renal cancer ^[31], gastric cancer ^[32]
JAG1	Biliary/renal epithelium, endocardium, hepatic stellate cells, CAFs	Organogenesis (liver/kidney/heart), immune modulation, fibrosis	Alagille syndrome ^[33], renal fibrosis ^[34], triple-negative breast cancer ^[35]
JAG2	Osteoblasts, placental trophoblasts, T cells, cardiac valves	Bone development, T-cell tolerance	Colorectal cancer ^[36], multiple myeloma ^[37], lung cancer ^[38]

Spotlight on Key Targets

DLL3: A Star Target in Small Cell Lung Cancer

DLL3 is overexpressed in more than 80% of small cell lung cancer (SCLC) cases and is virtually absent in normal adult tissues, making it an ideal tumor-specific antigen.

Mechanistic Insight: As an atypical ligand, DLL3 localizes to the Golgi apparatus and cell membrane and suppresses canonical Notch signaling in trans, promoting a neuroendocrine phenotype.

Clinical Progress:

Rovalpituzumab tesirine (Rova-T): The first DLL3-targeting antibody-drug conjugate (ADC); although it did not meet primary endpoints in Phase III, it validated DLL3 as a druggable target.
Tarlatamab (BiTE bispecific T-cell engager): Granted FDA Breakthrough Therapy Designation in 2024 for relapsed SCLC, with an objective response rate exceeding 40%.
Multiple DLL3-targeted bispecific antibodies, ADCs, and CAR-T therapies are now in clinical development, demonstrating significant therapeutic potential.

View all DLL3-related products

DLL4: The Key Switch Regulating Tumor Vascular Fate

DLL4 acts as a negative regulator during angiogenesis—activating Notch1 on endothelial cells to suppress excessive sprouting and maintain vascular network integrity. However, in multiple solid tumors (e.g., breast, colorectal, and liver cancers), DLL4 is aberrantly overexpressed, leading to disorganized, poorly perfused tumor vasculature that promotes hypoxia, invasion, and immune evasion.

Mechanistic Insight: Targeting DLL4 induces "non-functional angiogenesis"—increasing vessel density while disrupting maturation, exacerbating intratumoral hypoxia and inhibiting tumor growth. Importantly, DLL4 inhibition can remodel the tumor immune microenvironment, enhance T-cell infiltration, and synergize with immune checkpoint inhibitors (e.g., anti-PD-1).

Clinical Progress:

The most advanced DLL4-targeted agent is Navicixizumab (OncoMed), a DLL4/VEGF bispecific antibody currently in Phase III trials for platinum-resistant ovarian cancer.

View all DLL4-related products

Featured Products

The Notch signaling pathway plays a central regulatory role in key biological processes including development, tissue homeostasis, and tumorigenesis. In-depth investigation of this pathway relies on highly specific and reliable experimental reagents.

CUSABIO offers a comprehensive portfolio of antibodies, recombinant proteins, and ELISA kits covering the entire Notch receptor and ligand family, empowering your research with precision and efficiency.

● Partial Data Showcase

DLL3 Recombinant Monoclonal Antibody

Code: CSB-RA882142MA2HU

The Binding Activity of Human DLL3 with Anti-DLL3 recombinant antibody
Activity: Measured by its binding ability in a functional ELISA. Immobilized Human DLL3 (CSB-MP882142HU2d7) at 2 μg/mL can bind Anti-DLL3 recombinant antibody. The EC₅₀ is 3.990-4.723 ng/mL.

SHP-77 cells were stained with Human IgG1&Igκ Isotype Control (CSB-RA011156MA1HU)(green line) and anti-DLL3 antibody (CSB-RA882142MA2HU) (2µg/1*10⁶cells) (red line), washed and then followed by APC-conjugated anti-Human IgG Fc antibody and analyzed with flow cytometry.

The purity of DLL3 was greater than 95% as determined by SEC-HPLC

Recombinant Human Delta-like protein 3 (DLL3), partial (Active)

Code: CSB-MP882142HU

(Tris-Glycine gel) Discontinuous SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.

Activity: Measured by its binding ability in a functional ELISA. Immobilized DLL3 at 2 μg/ml can bind Anti-DLL3 Recombinant Antibody（CSB-RA882142A1HU）, the EC₅₀ is 1.102-1.707 ng/mL.

Human Delta-like protein 3(DLL3) ELISA kit

Code: CSB-EL006948HU

These standard curves are provided for demonstration only. A standard curve should be generated for each set of samples assayed.

● Product Catalog

Recombinant Protein

Target	Code	Product Name	Source
DLL3	CSB-EP882142HU	Recombinant Human Delta-like protein 3 (DLL3), partial	E.coli
DLL3	CSB-YP882142HU	Recombinant Human Delta-like protein 3 (DLL3), partial	Yeast
DLL3	CSB-EP882142HU1	Recombinant Human Delta-like protein 3 (DLL3), partial	E.coli
DLL3	CSB-MP882142HU	Recombinant Human Delta-like protein 3 (DLL3), partial (Active)	Mammalian cell
DLL3	CSB-MP3536MOV	Recombinant Macaca fascicularis Delta-like protein 3 (DLL3), partial (Active)	Mammalian cell
DLL3	CSB-EP882142HU2-B	Recombinant Human Delta-like protein 3 (DLL3), partial, Biotinylated	E.coli
DLL3	CSB-MP882142HU2	Recombinant Human Delta-like protein 3 (DLL3), partial (Active)	Mammalian cell
DLL3	CSB-MP882142HU2d7	Recombinant Human Delta-like protein 3 (DLL3), partial (Active)	Mammalian cell
DLL3	CSB-MP882142HU3	Recombinant Human Delta-like protein 3 (DLL3), partial (Active)	Mammalian cell
DLL3	CSB-MP882142HU3d7	Recombinant Human Delta-like protein 3 (DLL3), partial (Active)	Mammalian cell
DLL4	CSB-MP878862HU	Recombinant Human Delta-like protein 4 (DLL4), partial (Active)	Mammalian cell
DLL4	CSB-MP7292MOV-C	Recombinant Macaca fascicularis Delta-like protein (DLL4), partial	Mammalian cell
Jag1	CSB-EP870758MO	Recombinant Mouse Protein jagged-1 (Jag1), partial	E.coli
JAG1	CSB-MP011927HUh6	Recombinant Human Protein jagged-1 (JAG1), partial	Mammalian cell
NOTCH1	CSB-EP015949HU	Recombinant Human Neurogenic locus notch homolog protein 1 (NOTCH1), partial	E.coli
NOTCH2NLB	CSB-BP3322HU	Recombinant Human Notch homolog 2 N-terminal-like protein B (NOTCH2NLB)	Baculovirus
NOTCH2NLB	CSB-EP3322HU	Recombinant Human Notch homolog 2 N-terminal-like protein B (NOTCH2NLB)	E.coli

Antibody

Target	Code	Product Name	Tested Applications
DLL1	CSB-PA006947GA01HU	DLL1 Antibody	ELISA, WB
DLL3	CSB-RA882142MA2HU	DLL3 Recombinant Monoclonal Antibody	ELISA, FC
DLL3	CSB-PA882142LA01HU	DLL3 Antibody	ELISA, IHC
DLL3	CSB-PA882142LB01HU	DLL3 Antibody, HRP conjugated	ELISA
DLL3	CSB-PA882142LC01HU	DLL3 Antibody, FITC conjugated	N/A
DLL3	CSB-PA882142LD01HU	DLL3 Antibody, Biotin conjugated	ELISA
DLL4	CSB-PA073786	DLL4 Antibody	ELISA, IHC
DLL4	CSB-PA831848	DLL4 Antibody	ELISA, IHC
DLL4	CSB-PA006949LA01HU	DLL4 Antibody	ELISA, IF
DLL4	CSB-PA006949LB01HU	DLL4 Antibody, HRP conjugated	ELISA
DLL4	CSB-PA006949LC01HU	DLL4 Antibody, FITC conjugated	N/A
DLL4	CSB-PA006949LD01HU	DLL4 Antibody, Biotin conjugated	ELISA
JAG1	CSB-RA272247A0HU	JAG1 Recombinant Monoclonal Antibody	ELISA, IHC
JAG1	CSB-PA005638	JAG1 Antibody	WB, ELISA
JAG1	CSB-PA969766	JAG1 Antibody	ELISA, IHC
JAG1	CSB-PA234352	JAG1 Antibody	ELISA, IHC
JAG1	CSB-PA01949A0Rb	JAG1 Antibody	ELISA, IHC, IF
JAG1	CSB-PA01949B0Rb	JAG1 Antibody, HRP conjugated	ELISA
JAG1	CSB-PA01949C0Rb	JAG1 Antibody, FITC conjugated	N/A
JAG1	CSB-PA01949D0Rb	JAG1 Antibody, Biotin conjugated	ELISA

1
2
3

ELISA Kit

Target	Code	Product Name	Detection Range	Sensitivity
DLL1	CSB-EL006947HU	Human Delta-like protein 1(DLL1) ELISA kit	31.25 pg/ml - 2000 pg/ml	7.8 pg/ml
DLL3	CSB-EL006948HU	Human Delta-like protein 3(DLL3) ELISA kit	18.75 pg/mL-1200 pg/mL	4.68 pg/mL
DLL4	CSB-EL006949HU	Human Delta-like protein 4(DLL4) ELISA kit	23.5 pg/mL-1500 pg/mL	5.8 pg/mL
DLL4	CSB-EL006949MO	Mouse Delta-like protein 4(DLL4) ELISA kit	0.16 ng/ml-10 ng/ml	0.04ng/ml
JAG1	CSB-EL011927HU	Human Protein jagged-1(JAG1) ELISA kit	0.156 ng/mL-10 ng/mL	0.039 ng/mL
NOTCH1	CSB-EL015949HU	Human Neurogenic locus notch homolog protein 1(NOTCH1) ELISA kit	78 pg/mL-5000 pg/mL	19.5 pg/mL
NOTCH3	CSB-EL015952HU	Human Neurogenic locus notch homolog protein 3(NOTCH3) ELISA kit	125 pg/mL-8000 pg/mL	31.25 pg/mL

References

[1] Li X,Yan X,Wang Y, et al. The Notch signaling pathway: a potential target for cancer immunotherapy. J Hematol Oncol. 2023;16 (1):45.

[2] Herranz D,Ambesi-Impiombato A,Palomero T, et al. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat Med. 2014;20 (10):1130-7.

[3] Bertulfo K,Perez-Duran P,Miller H, et al. Therapeutic targeting of the NOTCH1 and neddylation pathways in T cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2025;122 (14):e2426742122.

[4] Lei JH,Xu J,Lyu X, et al. NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation. Nat Commun. 2020;11 (1):3256.

[5] Qiu H,Zmina PM,Huang AY, et al. Inhibiting Notch1 enhances immunotherapy efficacy in melanoma by preventing Notch1 dependent immune suppressive properties. Cancer Lett. 2018;434:144-151.

[6] Lindblad KE,Donne R,Liebling I, et al. NOTCH1 Drives Sexually Dimorphic Immune Responses in Hepatocellular Carcinoma. Cancer Discov. 2025;15 (3):495-510.

[7] Lu Y,Cao Y,Guo X, et al. Notch-Targeted Therapeutic in Colorectal Cancer by Notch1 Attenuation Via Tumor Microenvironment-Responsive Cascade DNA Delivery. Adv Healthc Mater. 2024;13 (22):e2400797.

[8] Hubmann R,Schwarzmeier JD,Shehata M, et al. Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood. 2002;99 (10):3742-7.

[9] Nayak R,Booker MA,Wang T, et al. Loss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer. Dev Cell. 2025;60 (24):3462-3479.e13.

[10] Xu J,Xu W,Yang X, et al. LncRNA MIR99AHG mediated by FOXA1 modulates NOTCH2/Notch signaling pathway to accelerate pancreatic cancer through sponging miR-3129-5p and recruiting ELAVL1. Cancer Cell Int. 2021;21 (1):674.

[11] Lee GH,Yoo KC,An Y, et al. FYN promotes mesenchymal phenotypes of basal type breast cancer cells through STAT5/NOTCH2 signaling node. Oncogene. 2018;37 (14):1857-1868.

[12] Heidari P,Taghizadeh M,Vakili O. Signaling pathways and molecular mechanisms involved in the onset and progression of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); a focus on Notch3 signaling. J Headache Pain. 2025;26 (1):96.

[13] Cardinale CJ,Li D,Tian L, et al. Association of a rare NOTCH4 coding variant with systemic sclerosis: a family-based whole exome sequencing study. BMC Musculoskelet Disord. 2016;17 (1):462.

[14] Bonyadi Rad E,Hammerlindl H,Wels C, et al. Notch4 Signaling Induces a Mesenchymal-Epithelial-like Transition in Melanoma Cells to Suppress Malignant Behaviors. Cancer Res. 2016;76 (7):1690-7.

[15] Gramantieri L,Giovannini C,Lanzi A, et al. Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma. Liver Int. 2007;27 (7):997-1007.

[16] Harb H,Chatila TA. Recent patents in allergy and immunology: Method for treating asthma or allergic disease via anti-Notch4 mAb. Allergy.

[17] Li M,Su B. Up-regulation of NOTCH4 gene expression in bipolar disorder: future studies. Am J Psychiatry. 2013;170 (5):560-1.

[18] Simpson MA,Irving MD,Asilmaz E, et al. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet. 2011;43 (4):303-5.

[19] McDaniell R,Warthen DM,Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006;79 (1):169-73.

[20] Brai E,Alina Raio N,Alberi L. Notch1 hallmarks fibrillary depositions in sporadic Alzheimer's disease. Acta Neuropathol Commun. 2016;4 (1):64.

[21] Singh S,Weindorfer C,Nandi A, et al. DLL1-responsive PD-L1 + tumor-associated macrophages promote endocrine resistance in breast cancer. Sci Transl Med. 2025;17 (823):eadr6207.

[22] Xu Y,Qiu Z,Chen J, et al. LINC00460 promotes neuroblastoma tumorigenesis and cisplatin resistance by targeting miR-149-5p/DLL1 axis and activating Notch pathway in vitro and in vivo. Drug Deliv Transl Res. 2024;14 (7):2003-2018.

[23] Xu D,Hu J,Xu S, et al. Dll1/Notch activation accelerates multiple myeloma disease development by promoting CD138+ MM-cell proliferation. Leukemia. 2012;26 (6):1402-5.

[24] Su PL,Chakravarthy K,Furuya N, et al. DLL3-guided therapies in small-cell lung cancer: from antibody-drug conjugate to precision immunotherapy and radioimmunotherapy. Mol Cancer. 2024;23 (1):97.

[25] Rudin CM,Reck M,Johnson ML, et al. Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer. J Hematol Oncol. 2023;16 (1):66.

[26] Owen DH,Giffin MJ,Bailis JM, et al. DLL3: an emerging target in small cell lung cancer. J Hematol Oncol. 2019;12 (1):61.

[27] Hermans BCM,Derks JL,Thunnissen E, et al. DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile. Lung Cancer. 2019;138:102-108.

[28] Naseri M,Saeednejad Zanjani L,Vafaei S, et al. Increased cytoplasmic expression of DLL4 is associated with favorable prognosis in colorectal cancer. Future Oncol. 2021;17 (24):3231-3242.

[29] Yan J,Xie Y,Liu Z, et al. DLL4-targeted CAR-T therapy sensitizes neoadjuvant chemotherapy via eliminating cancer stem cells and reshaping immune microenvironment in HER2 + breast cancer. J Immunother Cancer. 2024;12 (11):.

[30] Ding XY,Ding J,Wu K, et al. Cross-talk between endothelial cells and tumor via delta-like ligand 4/Notch/PTEN signaling inhibits lung cancer growth. Oncogene. 2012;31 (23):2899-906.

[31] Wang W,Hu W,Wang Y, et al. Long non-coding RNA UCA1 promotes malignant phenotypes of renal cancer cells by modulating the miR-182-5p/DLL4 axis as a ceRNA. Mol Cancer. 2020;19 (1):18.

[32] Afzalipour R,Abbasi-Dokht T,Sheikh M, et al. The Prediction of DLL4 as a Prognostic Biomarker in Patients with Gastric Cancer Using Anti-DLL4 Nanobody. J Gastrointest Cancer. 2024;55 (3):1380-1387.

[33] Gilbert MA,Keefer-Jacques E,Jadhav T, et al. Functional characterization of 2,832 JAG1 variants supports reclassification for Alagille syndrome and improves guidance for clinical variant interpretation. Am J Hum Genet. 2024;111 (8):1656-1672.

[34] Li G,Liu B,Yang H, et al. Omega-3 polyunsaturated fatty acids alleviate renal fibrosis in chronic kidney disease by reducing macrophage activation and infiltration through the JAG1-NOTCH1/2 pathway. Int Immunopharmacol. 2025;152:114454.

[35] Li C,Wang X,Shi D, et al. RFX5 promotes the progression of triple-negative breast cancer through transcriptional activation of JAG1. Hum Cell. 2025;38 (3):86.

[36] Vaish V,Kim J,Shim M. Jagged-2 (JAG2) enhances tumorigenicity and chemoresistance of colorectal cancer cells. Oncotarget. 2017;8 (32):53262-53275.

[37] Ghoshal P,Nganga AJ,Moran-Giuati J, et al. Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma. Cancer Res. 2009;69 (10):4380-7.

[38] Mandula JK,Sierra-Mondragon RA,Chang D, et al. Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages. Immunity. 2024;57 (5):1124-1140.e9.