NGFR - nerve growth factor receptor | Elisa - Clia - Antibody - Protein

Background

The nerve growth factor receptor (NGFR), also known as p75^NTR or CD271, is a receptor in the tumor necrosis factor receptor superfamily (TNFRSF) with critical roles in neuronal survival, differentiation, apoptosis, and regenerative processes. NGFR is primarily recognized for binding to nerve growth factor (NGF) but is also responsive to other neurotrophins, including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). NGFR serves as a high-affinity receptor, particularly in conjunction with Trk receptors and sortilin, with functions ranging from promoting neuronal survival to facilitating apoptosis, depending on the cellular context and ligand interaction.

NGFR has diverse roles beyond the nervous system, including in immune regulation, inflammatory responses, and tissue repair. In non-neuronal tissues, NGFR is involved in cell survival, migration, and differentiation. Due to its versatile functions, NGFR is implicated in neurodegenerative diseases, peripheral neuropathy, and various cancers, including melanoma and glioblastoma, where it often contributes to tumor progression and resistance to apoptosis.

Protein Structure

NGFR is a type I transmembrane glycoprotein with a structure that reflects its complex signaling and binding capabilities. Its structure is divided into distinct domains, each with specific functions that mediate ligand binding, receptor dimerization, and downstream signaling:

Extracellular Domain (ECD):

• The extracellular domain of NGFR is composed of four cysteine-rich domains (CRDs). These CRDs are characteristic of the TNF receptor superfamily and enable NGFR to bind neurotrophins and form complexes with other receptors.
• The presence of these CRDs enables NGFR to interact not only with NGF and other neurotrophins but also with co-receptors such as Trk receptors and sortilin, thereby allowing NGFR to facilitate a variety of signaling cascades based on the ligand and receptor configuration.

Transmembrane Domain (TMD):

• The transmembrane region of NGFR anchors the receptor in the cell membrane and plays a key role in stabilizing receptor dimerization and interactions with other transmembrane proteins, especially TrkA.
• This domain is vital for NGFR's ability to recruit and organize signaling complexes in response to ligand binding, affecting the subsequent intracellular signaling.

Intracellular Death Domain (DD):

• The intracellular domain of NGFR contains a death domain that is essential for its apoptotic signaling functions. However, NGFR lacks intrinsic kinase activity, meaning it relies on adaptor proteins to propagate intracellular signals.
• This domain enables NGFR to activate downstream pathways leading to apoptosis, differentiation, or survival, depending on the cellular context and whether other co-receptors or adaptors are present.

The distinct domains of NGFR allow it to engage in diverse signaling pathways, leading to different cellular responses based on ligand binding, receptor dimerization, and associated adaptors.

Classification and Subtypes

NGFR is classified as part of the tumor necrosis factor receptor superfamily (TNFRSF). Unlike other members of this family, NGFR does not have intrinsic signaling capabilities and requires co-receptors such as Trk receptors (e.g., TrkA) or sortilin to mediate its functions. There are no direct subtypes of NGFR; however, its activity is highly context-dependent, as it functions differently when in complex with various co-receptors.

Trk Receptors:

• NGFR often forms a high-affinity complex with TrkA in the presence of NGF, leading to cell survival and differentiation.

Sortilin:

• NGFR can bind with sortilin to promote apoptotic signaling, particularly when interacting with pro-neurotrophins, thus balancing survival and cell death.

Function and Biological Significance

NGFR plays a versatile role in the central and peripheral nervous systems and has functions in other tissues related to cell survival, apoptosis, and regeneration:

Neuronal Survival and Differentiation:

• NGFR mediates survival signals in neurons, particularly when associated with TrkA in the presence of NGF, promoting differentiation, survival, and axonal growth.
• This process is crucial during development and nerve repair, where NGFR-TrkA complexes help maintain neuronal populations and enhance recovery after injury.

Apoptotic Signaling:

• In the absence of TrkA or in complex with sortilin, NGFR often promotes apoptotic pathways. This is particularly significant in situations where NGFR binds to pro-neurotrophins (e.g., proNGF), which preferentially activate apoptosis.
• This apoptotic function plays a critical role in neural pruning during development and in controlling damaged or dysfunctional cells in both neural and non-neural tissues.

Non-Neuronal Roles:

• NGFR also has functions in non-neuronal tissues, where it regulates cell migration, adhesion, and differentiation. For example, in immune cells and mesenchymal stem cells, NGFR influences migration and cytokine production.
• The receptor is also involved in wound healing and regeneration, making it a target of interest in regenerative medicine.

Dual Role in Cancer:

• NGFR is implicated in various cancers, where it can promote survival and resistance to cell death in tumor cells. Its expression is upregulated in malignancies such as melanoma, glioblastoma, and breast cancer.
• In some cancers, NGFR’s apoptotic potential may be suppressed, leading to tumor progression. Conversely, NGFR-targeting therapies aim to restore its apoptotic function to aid in cancer treatment.

Clinical Issues

The diverse signaling pathways of NGFR make it relevant in several clinical conditions, including neurodegenerative diseases, cancer, and injury repair:

Neurodegenerative Diseases:

• NGFR is involved in neurodegenerative conditions like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). In these diseases, imbalances in NGFR signaling may contribute to the loss of neuronal survival and excessive apoptosis.
• Modulating NGFR interactions with neurotrophins or co-receptors offers therapeutic potential for neurodegenerative diseases, aiming to restore neuronal survival pathways or mitigate excessive cell death.

Cancer:

• NGFR is frequently overexpressed in cancers, such as melanoma, glioblastoma, and breast cancer. In these cases, NGFR aids in cancer cell survival, invasiveness, and resistance to chemotherapy.
• Therapeutic strategies targeting NGFR in cancer seek to disrupt its role in tumor cell survival and promote apoptosis, thereby enhancing the effectiveness of existing treatments.

Peripheral Neuropathy and Nerve Injury:

• NGFR’s role in nerve regeneration has made it a target for peripheral neuropathy and nerve injury repair. Enhancing NGFR activity or its signaling through TrkA can potentially promote nerve regeneration and recovery.
• Therapies focusing on NGFR in nerve repair aim to leverage its regenerative properties, facilitating functional recovery in peripheral nerve injuries.

Autoimmune and Inflammatory Conditions:

• NGFR is also relevant in autoimmune diseases, particularly where it influences immune cell migration and cytokine release. Modulating NGFR in these contexts could help in developing treatments to reduce inflammation and tissue damage.

Summary

NGFR (CD271) is a critical receptor in the tumor necrosis factor receptor superfamily, with essential roles in both the nervous system and other tissues. Structurally, NGFR comprises four cysteine-rich extracellular domains, a single-pass transmembrane domain, and an intracellular death domain. This structure allows NGFR to bind neurotrophins and engage in versatile signaling pathways, mediated through co-receptors like TrkA and sortilin.

Functionally, NGFR balances neuronal survival and apoptosis, influenced by its ligand-binding partners and cellular context. Its ability to mediate opposing outcomes based on ligand availability and receptor configuration makes it crucial for development, neuroprotection, and injury response. Beyond the nervous system, NGFR impacts immune cell migration, tissue repair, and inflammatory responses. In cancer, NGFR’s role in cell survival and resistance to apoptosis contributes to tumor progression, making it a target in cancer therapies. Additionally, NGFR’s function in neurodegenerative diseases and nerve injury highlights its therapeutic relevance in neuroprotection and regenerative medicine.

Given its diverse roles, NGFR remains a target of interest for treating conditions ranging from neurodegeneration and peripheral neuropathy to cancer and autoimmune diseases. Understanding its structure and signaling interactions offers promising avenues for developing targeted therapies that can modulate NGFR’s role in health and disease.