JAG1 - jagged canonical Notch ligand 1 |Elisa - Clia - Antibody - Protein

Background

Jagged-1 (JAG1) is a critical ligand within the Notch signaling pathway, a key cell-to-cell communication mechanism that regulates cellular differentiation, proliferation, and apoptosis. This pathway is pivotal during embryonic development and maintains tissue homeostasis in adults. JAG1, specifically, is one of the five canonical Notch ligands (alongside JAG2, DLL1, DLL3, and DLL4) and is highly involved in multiple developmental processes such as neurogenesis, vasculogenesis, and skeletal development. The interaction of JAG1 with Notch receptors triggers a series of proteolytic cleavages and releases the Notch intracellular domain (NICD), which translocates to the nucleus and activates target gene transcription. Dysregulation of JAG1 or aberrations in the Notch pathway are linked to congenital disorders, cancers, and other pathological conditions. In particular, mutations in JAG1 are associated with Alagille syndrome, a multisystem disorder affecting the liver, heart, and other organs.

Protein Structure

The structure of JAG1 is complex, with multiple functional domains that facilitate its interaction with Notch receptors and mediate its activity within the cell:

Extracellular Domain:

• Signal Peptide: JAG1 is initially synthesized as a precursor protein with a signal peptide, which directs it to the endoplasmic reticulum for further processing and secretion.
• DSL (Delta/Serrate/Lag-2) Domain: This critical region mediates the binding of JAG1 to Notch receptors. Located near the N-terminus, the DSL domain contains essential residues that engage with Notch receptors and initiate signaling.
• EGF-like Repeats: The extracellular region of JAG1 contains approximately 16 epidermal growth factor (EGF)-like repeats. These repeats are characterized by a conserved sequence that stabilizes the protein structure through disulfide bonds. Specific EGF-like repeats, particularly the fifth and sixth repeats, are important for high-affinity binding to Notch receptors, while others help maintain protein stability and interaction versatility.
• Calcium-binding Sites: Several EGF-like domains in JAG1 are calcium-binding, which contributes to the protein’s structural integrity and ligand-receptor interactions.

Transmembrane Domain:

• The transmembrane domain anchors JAG1 to the cell membrane, orienting its extracellular domain outward for interaction with Notch receptors on adjacent cells. This domain spans the lipid bilayer and plays a role in the localization and stability of JAG1 within the membrane.

Intracellular Domain:

• JAG1’s intracellular domain is relatively short and lacks known intrinsic signaling motifs, differentiating it from some other signaling receptors. However, this domain is involved in interacting with cytosolic proteins and influences JAG1’s stability, trafficking, and potential feedback regulation within the cell. Studies suggest that post-translational modifications, such as phosphorylation, may occur here and influence the protein’s turnover rate or subcellular localization.

Classification and Subtypes

JAG1 is part of the Notch ligand family, specifically the Jagged subfamily, which includes two members: JAG1 and JAG2. These ligands are distinct from the Delta-like ligands (DLL1, DLL3, and DLL4) in their ability to bind multiple Notch receptors and their unique structural features, such as more extensive EGF-like repeats. No additional isoforms or subtypes of JAG1 have been identified; however, alternative splicing events or post-translational modifications, such as glycosylation, can influence JAG1’s interaction with Notch receptors. This classification helps separate Jagged ligands from Delta-like ligands due to their differential roles in developmental pathways and tissue-specific expression.

Function and Biological Significance

Activation of Notch Signaling:

• JAG1’s primary function is to bind Notch receptors (NOTCH1-4) on adjacent cells, activating the Notch signaling cascade. Upon binding, the receptor undergoes two sequential cleavages: the first by ADAM family metalloproteases, and the second by γ-secretase. This process releases the NICD, which translocates to the nucleus and activates transcription of target genes, including Hes1, Hey1, and Hey2, which are crucial for regulating cell fate.
• The activation of Notch signaling by JAG1 influences numerous developmental processes, including the differentiation of neural progenitors, formation of vascular structures, and specification of various cell lineages.

Role in Development:

• Neurogenesis: JAG1 is vital for the development of the nervous system, where it regulates the balance between neuronal and glial cell differentiation. By activating Notch signaling, JAG1 helps control the timing of neurogenesis and the maintenance of neural stem cells.
• Vasculogenesis and Angiogenesis: In endothelial cells, JAG1-Notch interactions are essential for the formation and remodeling of blood vessels. Through Notch signaling, JAG1 modulates angiogenesis and vascular stability, as well as the differentiation of smooth muscle cells from mesenchymal precursors.
• Hematopoiesis: JAG1 plays a role in the hematopoietic stem cell niche, influencing stem cell maintenance, differentiation, and lineage specification, particularly in T-cell and myeloid lineages.
• Skeletal and Cardiac Development: In bone development, JAG1 is involved in the differentiation of osteoblasts, while in the heart, it helps regulate the formation of cardiac valves and septa, influencing congenital heart defect risk in cases of JAG1 mutation.

Cellular Processes:

• JAG1-Notch signaling modulates several cellular processes beyond differentiation, including cell proliferation, apoptosis, and immune cell function. JAG1-Notch signaling has been shown to contribute to cell adhesion, migration, and cellular interactions within the immune system, particularly in T cell activation and differentiation.

Clinical Issues

Alagille Syndrome:

• Mutations in the JAG1 gene are the primary cause of Alagille syndrome, an autosomal dominant disorder affecting the liver, heart, and other organs. This syndrome is characterized by bile duct paucity, leading to liver dysfunction, as well as congenital heart defects, characteristic facial features, and vertebral abnormalities. Alagille syndrome highlights JAG1’s critical roles in bile duct development, cardiac formation, and bone formation.
• Most JAG1 mutations in Alagille syndrome are loss-of-function, which results in reduced Notch signaling and disrupted tissue patterning during embryogenesis. Genetic testing for JAG1 mutations is an important diagnostic tool for Alagille syndrome.

Cancer:

• Dysregulated JAG1 expression has been implicated in various cancers, including breast, prostate, and liver cancers. Overexpression of JAG1 can promote tumor cell survival, metastasis, and resistance to apoptosis, making it a potential target for anti-cancer therapies. In breast cancer, for example, high JAG1 expression is associated with poor prognosis due to its role in maintaining cancer stem cell populations and promoting epithelial-to-mesenchymal transition (EMT).
• Therapies targeting JAG1-Notch signaling are being investigated, including γ-secretase inhibitors, which block Notch activation, and monoclonal antibodies that specifically inhibit JAG1 or its interaction with Notch receptors.

Cardiovascular Diseases:

• Given JAG1’s role in vascular and cardiac development, altered JAG1 expression or function may contribute to cardiovascular diseases. Abnormal JAG1-Notch signaling has been linked to pulmonary arterial hypertension and other vascular disorders. Research is ongoing to determine how JAG1-targeted therapies might modulate vascular health or treat these conditions.

Inflammatory and Fibrotic Disorders:

• JAG1 has been implicated in fibrotic diseases due to its influence on cellular differentiation and migration in fibroblasts. Abnormal JAG1 expression is associated with hepatic and pulmonary fibrosis, where it may contribute to excessive collagen deposition and tissue remodeling. Inhibiting JAG1-Notch signaling is being explored as a potential therapeutic strategy in fibrotic diseases.

Neurological Disorders:

• Due to JAG1’s involvement in neurogenesis, its dysregulation is being studied in neurodegenerative diseases and developmental neurological disorders. In diseases where abnormal Notch signaling occurs, JAG1’s expression and activity may serve as therapeutic targets to influence neurogenesis or neuronal survival.

Summary

Jagged-1 (JAG1) is a Notch ligand that serves essential functions in cellular differentiation, tissue development, and immune cell function through its activation of the Notch signaling pathway. Structurally, JAG1 is a transmembrane protein composed of a signal peptide, DSL domain, EGF-like repeats, a transmembrane region, and a short intracellular tail. These domains contribute to JAG1’s ability to bind Notch receptors on neighboring cells, facilitating proteolytic activation and nuclear signaling via the Notch intracellular domain (NICD). The activation of Notch signaling by JAG1 is involved in several developmental processes, including neurogenesis, angiogenesis, hematopoiesis, and skeletal development, underscoring its importance in embryonic growth and adult tissue homeostasis.

Clinically, mutations in JAG1 are linked to Alagille syndrome, a multisystem developmental disorder, and dysregulation of JAG1-Notch signaling has been implicated in cancers, cardiovascular diseases, and fibrosis. Overexpression of JAG1 in cancers is associated with poor prognosis, promoting tumor growth, EMT, and metastasis. Efforts to modulate JAG1 signaling, particularly in cancer and fibrotic diseases, are being investigated as potential therapeutic interventions.