LIFR - LIF receptor subunit alpha | Elisa - Clia - Antibody - Protein

Background

The leukemia inhibitory factor receptor (LIFR), also known as the LIF receptor subunit alpha, is a component of a cytokine receptor complex responsible for mediating the effects of the leukemia inhibitory factor (LIF). LIF is part of the interleukin-6 (IL-6) family of cytokines and is involved in various cellular processes, such as cell survival, proliferation, and differentiation, particularly in neuronal, hematopoietic, and reproductive cells. LIFR is encoded by the LIFR gene, located on chromosome 5p13, and is widely expressed across various tissues, including the placenta, brain, liver, and bone marrow.

LIFR functions as a non-signaling receptor subunit and, upon binding to LIF, associates with the co-receptor gp130. Together, this receptor complex initiates intracellular signaling pathways that are central to immune responses, tissue repair, and neural development. LIFR is significant in embryonic development and stem cell maintenance, and dysregulation of LIFR signaling is associated with several diseases, such as inflammatory disorders, cancer, and neurodegenerative diseases.

Protein Structure

The LIF receptor subunit alpha is a type I transmembrane glycoprotein, with a structure divided into three main domains that facilitate LIF binding and receptor complex formation:

Extracellular Domain:

The extracellular region is composed of cytokine-binding and immunoglobulin-like domains, crucial for ligand binding and dimerization.

Structurally, this domain has three primary subregions:

• Cytokine-binding homology module (CBM): The CBM includes a conserved motif involved in the interaction with LIF and subsequent recruitment of gp130. This homology module has two fibronectin type III domains, which form a binding pocket for LIF.
• Immunoglobulin-like domain: This domain contributes to structural stability and aids in binding specificity, facilitating the formation of the LIF-LIFR complex.
• Fibronectin type III repeats: These repeats are integral for protein stability, ensuring the proper alignment and positioning of the ligand-binding site.

Transmembrane Domain:

• LIFR contains a single-pass transmembrane domain that anchors the receptor to the cell membrane. This helical domain stabilizes the receptor and facilitates the alignment of extracellular and intracellular domains for proper signaling.

Intracellular Domain:

• The intracellular region of LIFR is essential for binding to gp130 and contains multiple tyrosine residues that are phosphorylated upon ligand binding, recruiting downstream signaling proteins.
• Unlike other receptors with intrinsic kinase activity, LIFR relies on associated kinases (such as Janus kinase 1 or JAK1) for signal transduction. Once phosphorylated, these tyrosine residues act as docking sites for various signaling proteins, including STAT3, STAT1, and ERK, initiating downstream pathways involved in cellular response.

The LIF-LIFR-gp130 complex formation induces conformational changes necessary for activation and stabilization, which triggers intracellular signaling cascades.

Classification and Subtypes

LIFR is part of the class I cytokine receptor family, which includes receptors for other interleukin-6 family cytokines. Although LIFR itself does not have major subtypes, it interacts with different receptors or signaling molecules in various contexts, such as in complex formation with oncostatin M receptor (OSMR). This allows the receptor to modulate diverse cellular processes based on the specific ligand-receptor pairing.

Function and Biological Significance

The LIF receptor, in combination with gp130, regulates several key cellular functions, with LIFR playing a crucial role in mediating LIF-induced biological responses:

Stem Cell Maintenance:

• LIF-LIFR signaling is instrumental in maintaining the pluripotency of embryonic stem cells (ESCs). Activation of STAT3 downstream of LIFR promotes self-renewal in ESCs, ensuring they remain undifferentiated.

Neuronal Development and Function:

• In the nervous system, LIFR supports neuronal survival and differentiation. It is particularly active in astrocytes and neurons, aiding in nerve regeneration after injury and offering neuroprotective effects.
• LIFR signaling is involved in the development of sensory neurons and glial cells, promoting neuronal repair and reducing apoptosis.

Bone Metabolism:

• LIFR plays an essential role in osteogenesis by modulating bone cell differentiation and proliferation, affecting osteoblast and osteoclast activity. It is involved in the maintenance of bone density and strength and impacts the response to mechanical stress in bones.

Reproductive System:

• LIFR is vital in reproductive biology, where LIF-LIFR signaling is essential for blastocyst implantation and pregnancy establishment. Proper functioning of this receptor-ligand system ensures the survival and development of the embryo post-implantation.

Immune Modulation:

• LIF-LIFR signaling modulates immune responses by influencing cytokine production and inflammatory pathways. It is particularly active in modulating macrophage function, where it enhances anti-inflammatory cytokine release, thus contributing to immune tolerance.

Clinical Issues

Alterations in LIFR expression and function are linked to several diseases:

1. Cancer:

• LIFR is known to function as a tumor suppressor in certain cancers, such as breast cancer and hepatocellular carcinoma (HCC). In these cancers, reduced expression or mutations in LIFR correlate with increased malignancy and poor prognosis.
• In breast cancer, for example, LIFR suppression disrupts STAT3 signaling, promoting metastasis and proliferation. Restoring LIFR activity is considered a therapeutic strategy to control tumor growth in certain malignancies.

1. Neurological Disorders:

• Dysregulation in LIFR signaling is associated with neurodegenerative diseases such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Insufficient LIFR activity can lead to decreased neuroprotection and increased neuronal apoptosis.
• Therapies targeting LIFR signaling pathways are under investigation to develop neuroprotective strategies for these disorders.

1. Bone and Skeletal Disorders:

• Defects in LIFR are implicated in bone diseases, including osteoporosis. Given its role in bone metabolism and osteogenesis, altered LIFR function disrupts bone density and increases susceptibility to fractures.
• LIFR deficiency in children can lead to skeletal dysplasia, a rare genetic disorder marked by abnormal bone growth, reduced bone density, and limb deformities.

1. Inflammatory Conditions:

• Since LIFR has anti-inflammatory effects, changes in its signaling can impact inflammatory diseases. Enhanced LIF-LIFR signaling in response to tissue damage or infection can reduce inflammation by modulating macrophage activity.
• Abnormal LIFR signaling has been observed in certain autoimmune disorders, though the mechanism is not yet fully elucidated. Understanding this interaction offers potential for therapies targeting inflammatory regulation in autoimmune conditions.

Summary

The leukemia inhibitory factor receptor subunit alpha (LIFR) is a transmembrane cytokine receptor in the class I cytokine receptor family. LIFR, when bound by leukemia inhibitory factor (LIF) and in association with the co-receptor gp130, forms a signaling complex that initiates diverse cellular processes essential for stem cell maintenance, neuronal development, bone metabolism, reproductive biology, and immune modulation. LIFR’s structure includes an extracellular domain with cytokine-binding and immunoglobulin-like domains, a transmembrane helical domain, and an intracellular domain that recruits signaling molecules like STAT3 upon activation.

LIFR signaling is critical for maintaining pluripotency in embryonic stem cells and plays a neuroprotective role in the nervous system, modulating repair mechanisms and neurogenesis. In bone metabolism, LIFR impacts osteogenesis and bone density maintenance. The receptor also plays roles in blastocyst implantation in reproduction and exerts anti-inflammatory effects within the immune system.

Clinically, LIFR dysfunction or altered expression is linked to cancers, especially breast and liver cancers, where it often functions as a tumor suppressor. Neurological disorders, such as ALS and Alzheimer’s, also correlate with reduced LIFR activity, which may lead to increased neuronal death and decreased regenerative capacity. Inflammatory conditions and bone diseases, including osteoporosis, have been associated with abnormal LIFR function.

Overall, LIFR is a significant receptor that regulates essential cellular processes, and its roles in health and disease make it a promising target for developing treatments for cancer, neurodegeneration, and inflammatory diseases.