TNFRSF12A - TNF receptor superfamily member 12A | Elisa - Clia - Antibody - Protein

Background

TNFRSF12A, also known as FN14 (Fibroblast Growth Factor Inducible 14), is a member of the tumor necrosis factor receptor superfamily (TNFRSF). This receptor is highly responsive to cellular stress signals, tissue damage, and inflammation, and it plays an essential role in tissue remodeling, inflammation, and wound healing. FN14 is particularly notable for its role as the primary receptor for TWEAK (TNF-like weak inducer of apoptosis), a member of the TNF superfamily of ligands.

The binding of TWEAK to TNFRSF12A activates various downstream signaling pathways that influence processes including cell survival, proliferation, migration, and apoptosis. Its expression is typically low in most normal tissues but is upregulated under stress conditions such as injury, inflammation, or exposure to growth factors. Elevated levels of TNFRSF12A have been observed in a variety of pathological conditions, particularly in inflammatory diseases, cancer, cardiovascular disease, and fibrosis, where its activity is often associated with promoting cell survival, angiogenesis, and tissue remodeling.

Protein Structure

The TNFRSF12A protein consists of several key structural features that facilitate its functions:

Extracellular Domain (ECD):

• TNFRSF12A is a type I transmembrane protein, with an extracellular domain that contains a single cysteine-rich domain (CRD). Unlike other TNF receptor family members that may have multiple CRDs, TNFRSF12A’s single CRD serves as the binding interface for TWEAK.
• The CRD is critical for ligand binding and specificity, allowing TNFRSF12A to interact specifically with TWEAK while differentiating it from other ligands in the TNF superfamily.

Transmembrane Domain (TMD):

• The transmembrane domain anchors TNFRSF12A in the cell membrane, facilitating signal transduction from extracellular TWEAK binding to intracellular signaling cascades. This single-pass domain stabilizes TNFRSF12A within the membrane, allowing its extracellular portion to be exposed to the ligand.

Intracellular Domain (ICD):

• The intracellular domain of TNFRSF12A lacks a death domain, a structural feature found in other TNFRSF members like TNFRSF10 and TNFRSF1 that typically mediates apoptotic signaling.
• Instead, the intracellular domain interacts with various intracellular adaptor proteins, such as TRAF (TNF receptor-associated factors), which transmit signals to downstream pathways, especially the NF-κB and MAPK pathways. These pathways lead to cellular responses like inflammation, survival, and tissue repair.
• Additionally, phosphorylation sites on the intracellular tail are essential for modulating the receptor's activity and enhancing its interactions with downstream signaling molecules.

This structural configuration allows TNFRSF12A to initiate non-apoptotic signaling, primarily promoting cellular survival and inflammatory responses in response to TWEAK.

Classification and Subtypes

TNFRSF12A is classified as part of the TNF receptor superfamily (TNFRSF), specifically binding the TNF-like cytokine TWEAK. While other TNF receptors typically include multiple CRDs and can engage several TNF ligands, TNFRSF12A is unique for its specific association with TWEAK and its solitary CRD structure.

There are no known subtypes or isoforms of TNFRSF12A. Its classification is distinguished by its ability to activate inflammatory and survival signaling, often in response to environmental stresses that upregulate TWEAK and FN14 expression.

Function and Biological Significance

Regulation of Cell Survival and Proliferation:

• TNFRSF12A is involved in promoting cellular survival under stress conditions by activating the NF-κB pathway, which leads to the expression of survival and anti-apoptotic genes. This activity is critical in tissue repair and cellular recovery from damage.
• In certain cancer contexts, this pathway is exploited by tumor cells, where TNFRSF12A signaling may contribute to uncontrolled proliferation and resistance to cell death.

Inflammatory Response:

• Through NF-κB and JNK (c-Jun N-terminal kinase) signaling, TNFRSF12A activation can also lead to the expression of pro-inflammatory cytokines and chemokines. This contributes to immune cell recruitment and activation, playing an essential role in inflammatory diseases such as rheumatoid arthritis and atherosclerosis.
• By promoting cytokine expression, TNFRSF12A contributes to a feedback loop that perpetuates inflammation and tissue remodeling in response to injury.

Tissue Repair and Fibrosis:

• TNFRSF12A activity is closely linked to tissue remodeling processes, making it significant in wound healing and fibrosis. TWEAK/TNFRSF12A signaling can stimulate the migration of fibroblasts and endothelial cells, which are crucial for tissue repair and angiogenesis.
• However, persistent or excessive activation of TNFRSF12A has been associated with pathological fibrosis in organs like the liver, kidneys, and lungs, as it promotes extracellular matrix (ECM) deposition and myofibroblast activation.

Angiogenesis:

• TNFRSF12A supports angiogenesis, especially in the context of ischemic or damaged tissues where new blood vessel formation is necessary for oxygen and nutrient delivery. The receptor can induce the expression of pro-angiogenic factors, such as VEGF (vascular endothelial growth factor), facilitating vascular growth.

Clinical Issues

Cancer:

• TNFRSF12A is frequently overexpressed in various cancers, including glioblastoma, breast cancer, and pancreatic cancer. Its pro-survival and pro-migratory functions enable cancer cells to resist apoptosis and metastasize.
• Elevated TNFRSF12A levels are often associated with aggressive tumor phenotypes and resistance to conventional therapies. As a result, the TWEAK/TNFRSF12A axis is being explored as a target for cancer therapies. Blocking this pathway could potentially reduce tumor growth and improve sensitivity to chemotherapy.

Inflammatory Diseases:

• Chronic activation of TNFRSF12A contributes to inflammatory and autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease, by perpetuating inflammatory cytokine production.
• In rheumatoid arthritis, TNFRSF12A expression in synovial tissue is linked with joint inflammation and tissue degradation, and inhibitors targeting the TWEAK/TNFRSF12A pathway are under investigation to manage these conditions.

Fibrotic Disorders:

• Pathological fibrosis, including pulmonary fibrosis, liver cirrhosis, and kidney fibrosis, is associated with aberrant TNFRSF12A activation. Excessive signaling leads to ECM accumulation, tissue stiffness, and loss of organ function.
• Experimental therapies targeting TNFRSF12A aim to mitigate fibrosis by reducing ECM production and fibroblast activity, slowing the progression of these diseases.

Cardiovascular Disease:

• TNFRSF12A is implicated in atherosclerosis and ischemia-related injuries. Its pro-inflammatory and angiogenic roles contribute to the formation of atherosclerotic plaques and the remodeling of vasculature in ischemic tissues. Blocking TWEAK/TNFRSF12A signaling in cardiovascular disease models has shown promise in reducing plaque formation and inflammatory damage in blood vessels.

Summary

TNFRSF12A, or FN14, is a TNF receptor superfamily member and the primary receptor for TWEAK. It plays a significant role in cell survival, proliferation, inflammation, and tissue remodeling. Structurally, TNFRSF12A includes a single cysteine-rich extracellular domain that binds TWEAK, a transmembrane domain that anchors it in the membrane, and a truncated intracellular domain that activates non-apoptotic signaling through pathways like NF-κB and MAPK. Unlike other TNF receptors, TNFRSF12A lacks a full death domain, resulting in a focus on survival and inflammation rather than apoptotic functions.

TNFRSF12A’s biological functions make it crucial in responses to tissue injury and stress, mediating processes that enable cell survival, inflammation, and tissue repair. Its pathological relevance is evident in diseases where these responses become dysregulated, including cancers, fibrotic diseases, chronic inflammatory disorders, and cardiovascular disease. Inhibiting the TWEAK/TNFRSF12A pathway is an area of active research, with therapeutic potential for conditions involving chronic inflammation, fibrosis, and tumor growth. As research advances, targeting TNFRSF12A may provide new strategies to manage these complex diseases by modulating its influence on cell survival, inflammation, and tissue remodeling.