GO:0140370 type II oncostatin-M receptor complex: Components, Assembly and Research Methods, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0140370 describes the type II oncostatin-M receptor complex, a heterodimeric cytokine receptor composed of gp130 (IL6ST) and LIFR that binds LIF and related cytokines.
• The complex is distinct from the type I OSM receptor (gp130/OSMR) and is conserved in humans and rats but differs in mice.
• Signaling through this complex activates JAK/STAT, MAPK, and PI3K pathways, influencing cell proliferation, differentiation, and survival.
• Dysregulation of the type II OSM receptor complex is implicated in inflammatory diseases, fibrosis, and cancer, including mammary carcinoma and cardiac pathology.
• Mutations in the related OSMR gene cause familial primary localized cutaneous amyloidosis, highlighting the clinical importance of OSM receptor complexes.
• CRISPR-based knockout, knock-in, and overexpression models are essential for dissecting the specific roles of gp130 and LIFR in health and disease.
Description
The type II oncostatin-M receptor complex (GO:0140370) is a heterodimeric cell surface receptor that mediates signaling by the cytokine leukemia inhibitory factor (LIF) and related cytokines such as oncostatin M (OSM). It is composed of the shared signal-transducing subunit gp130 (encoded by IL6ST) and the ligand-specific subunit LIFR. This complex is a key component of the interleukin-6 family cytokine signaling network, which regulates diverse biological processes including cell growth, differentiation, survival, and inflammation. Understanding its structure and function is critical for elucidating mechanisms of cytokine signaling and for developing targeted therapies for diseases such as cancer and inflammatory disorders. Recent structural studies have provided near-atomic resolution maps of the complete extracellular assemblies of type I and type II OSM receptor complexes, revealing how ligand binding induces conformational changes that trigger intracellular signaling. These insights are essential for researchers studying cytokine receptor biology and for those developing biologics or small molecules that modulate these pathways.
type II oncostatin-M receptor complex At A Glance
| GO ID | GO:0140370 |
|---|---|
| GO term | type II oncostatin-M receptor complex |
| Ontology | cellular_component |
| Synonym | leukemia inhibitory factor receptor complex, oncostatin-M receptor complex |
| Major function | Heterodimeric receptor for LIF and related cytokines, mediating JAK/STAT, MAPK, and PI3K signaling |
| Subunits | gp130 (IL6ST) and LIFR |
| Ligands | LIF, OSM, CT-1, CNTF, CLC |
| Conservation | Conserved in humans and rats; differs in mice |
| Related complex | Type I OSM receptor (gp130/OSMR) |
What Is GO:0140370?
The type II oncostatin-M receptor complex is a heterodimeric receptor for the cytokine LIF (leukemia inhibitory factor). In humans, the receptor complex is made up of the gene products gp130 and LIFR. This complex is also known as the leukemia inhibitory factor receptor complex or oncostatin-M receptor complex. It is a cellular component that functions in signal transduction from the cell surface to the cytoplasm and nucleus.
Why Is type II oncostatin-M receptor complex Important in Cell Biology?
The type II oncostatin-M receptor complex is a central node in the interleukin-6 family cytokine network, which controls fundamental processes such as cell proliferation, differentiation, survival, and inflammation. Its dysregulation is linked to a range of human diseases, including cancer, fibrosis, and inflammatory disorders. Moreover, structural and functional studies of this complex have provided critical insights into cytokine receptor activation mechanisms, guiding the development of therapeutic antibodies and small molecules. Therefore, understanding this complex is essential for both basic research and translational medicine.
• Mediates signaling by LIF and OSM, cytokines involved in embryonic development, hematopoiesis, and inflammation.
• Activates JAK/STAT, MAPK, and PI3K pathways, influencing gene expression and cell fate.
• Implicated in cancer progression, including mammary epithelial cell proliferation and survival.
• Plays a role in cardiac protection and regeneration, with potential therapeutic implications.
• Mutations in the related OSMR gene cause familial primary localized cutaneous amyloidosis.
• Serves as a target for therapeutic intervention in inflammatory diseases and cancer.
• Structural studies reveal unique activation mechanisms distinct from type I OSM receptor.
• Conservation in rats but differences in mice highlight species-specific considerations for preclinical models.
• Involved in lung epithelial cell regulation, with implications for respiratory diseases.
• Interleukin-31, a related cytokine, connects pruritus and cancer through shared receptor subunits.
Structure and Composition of type II oncostatin-M receptor complex
gp130 (IL6ST) subunit
In simple terms: gp130 is the shared signaling subunit used by many cytokines.
gp130, encoded by the IL6ST gene, is a transmembrane glycoprotein that serves as the common signal-transducing subunit for several interleukin-6 family cytokines. In the type II OSM receptor complex, gp130 pairs with LIFR to form a functional heterodimer. It contains extracellular immunoglobulin-like and cytokine-binding domains, a transmembrane region, and an intracellular domain that recruits JAK kinases and activates downstream signaling.
LIFR subunit
In simple terms: LIFR is the ligand-specific subunit that binds LIF and related cytokines.
LIFR (leukemia inhibitory factor receptor) is a transmembrane protein that provides ligand specificity to the type II OSM receptor complex. It binds LIF, OSM, cardiotrophin-1 (CT-1), ciliary neurotrophic factor (CNTF), and cardiotrophin-like cytokine (CLC). LIFR contains extracellular cytokine-binding domains and fibronectin type III domains, and its intracellular region interacts with JAK kinases to initiate signaling.
Heterodimer assembly
In simple terms: The two subunits come together only when the ligand is present.
The type II OSM receptor complex is assembled in a ligand-induced manner. In the absence of ligand, gp130 and LIFR are not stably associated. Binding of LIF or OSM to LIFR recruits gp130, leading to the formation of a functional heterodimer. Recent cryo-EM structures of the complete extracellular assemblies of type I and type II OSM receptor complexes have revealed the molecular details of this assembly, including the conformational changes that occur upon ligand binding.
Ligand binding and specificity
In simple terms: Different ligands can bind to this receptor, but the exact combination determines the signal.
The type II OSM receptor complex binds LIF with high affinity and also recognizes OSM, CT-1, CNTF, and CLC. The specificity is determined by the LIFR subunit, which discriminates among these cytokines. In contrast, the type I OSM receptor complex uses OSMR instead of LIFR and binds OSM but not LIF. This ligand-receptor specificity is critical for the distinct biological functions of these cytokines.
Species differences
In simple terms: The receptor works similarly in humans and rats, but differently in mice.
The type II OSM receptor complex is conserved between humans and rats, but the murine receptor differs in its ligand specificity and subunit composition. This species difference has important implications for preclinical studies using mouse models, as findings may not always translate directly to human biology.
Key Genes Involved in GO:0140370 type II oncostatin-M receptor complex
The following genes encode the core subunits and key signaling components of the type II oncostatin-M receptor complex, as well as related cytokines and regulators.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL6ST | Encodes gp130, the shared signal-transducing subunit | Knockout causes embryonic lethality; essential for signaling |
| LIFR | Encodes LIFR, the ligand-specific subunit | Mutations linked to Stüve-Wiedemann syndrome; key for LIF signaling |
| OSMR | Encodes OSMR, subunit of type I OSM receptor | Mutations cause familial primary localized cutaneous amyloidosis |
| LIF | Cytokine ligand for type II OSM receptor | Regulates stem cell pluripotency and inflammation |
| OSM | Cytokine ligand for both type I and type II receptors | Involved in inflammation, cancer, and cardiac remodeling |
| JAK1 | Janus kinase associated with gp130 | Mediates STAT activation downstream of receptor |
| JAK2 | Janus kinase associated with gp130 and LIFR | Mediates STAT activation downstream of receptor |
| STAT3 | Transcription factor activated by JAKs | Drives gene expression for proliferation and survival |
| STAT1 | Transcription factor activated by JAKs | Mediates inflammatory and antiviral responses |
| MAPK1 | Mitogen-activated protein kinase | Regulates proliferation and differentiation |
| MAPK3 | Mitogen-activated protein kinase | Regulates proliferation and differentiation |
| PIK3CA | Phosphatidylinositol 3-kinase catalytic subunit | Activates AKT pathway for survival |
| AKT1 | Serine/threonine kinase | Promotes cell survival and metabolism |
| SOCS3 | Suppressor of cytokine signaling | Negative feedback regulator of JAK/STAT |
| PTPN11 | Protein tyrosine phosphatase SHP2 | Modulates MAPK pathway downstream of receptor |
| IL31RA | Interleukin-31 receptor A | Forms receptor with OSMR for IL-31 signaling |
| CNTF | Ciliary neurotrophic factor | Ligand for LIFR-containing complexes |
How Is type II oncostatin-M receptor complex Regulated?
The type II oncostatin-M receptor complex is regulated at multiple levels. Expression of the receptor subunits gp130 and LIFR can be modulated by cytokines, growth factors, and cellular stress. For example, in lung-derived epithelial cells, type II OSM receptor expression is regulated by inflammatory mediators. At the signaling level, the complex is subject to negative feedback by SOCS proteins, particularly SOCS3, which binds to gp130 and inhibits JAK activity. Additionally, protein tyrosine phosphatases such as SHP2 (PTPN11) can attenuate signaling by dephosphorylating JAKs and STATs. The availability of ligands (LIF, OSM) also controls receptor activation. Understanding these regulatory mechanisms is crucial for targeting the pathway in disease.
type II oncostatin-M receptor complex and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL6ST | Inflammatory diseases, cancer | Knockout or knock-in in cell lines and mouse models |
| LIFR | Stüve-Wiedemann syndrome, cancer | Patient-derived iPSCs with LIFR mutations |
| OSMR | Familial primary localized cutaneous amyloidosis | Knock-in mouse models expressing mutant OSMR |
| LIF | Cancer, inflammation | Overexpression or knockout in tumor cell lines |
| OSM | Cardiac remodeling, cancer | Cardiomyocyte-specific knockout or overexpression |
Cancer
The type II oncostatin-M receptor complex is implicated in cancer biology. In mammary epithelial cells, oncostatin M-specific receptor expression and function regulate cell proliferation, with differential effects in normal versus malignant cells. Activation of the complex can promote proliferation and survival of cancer cells through STAT3 and MAPK pathways. In addition, interleukin-31, which signals through a related receptor complex containing OSMR, connects pruritus and cancer, highlighting the broader role of OSM receptor family in oncology.
Cardiovascular disease
Oncostatin M and its receptor complexes play a role in cardiomyocyte protection, regeneration, and failure. The type II OSM receptor complex, through LIFR, can activate protective signaling in the heart, but sustained activation may contribute to pathological remodeling and heart failure. Understanding the balance between protective and detrimental effects is an active area of research.
Inflammatory and fibrotic diseases
Dysregulated signaling through the type II OSM receptor complex is associated with chronic inflammatory diseases and fibrosis. LIF and OSM are elevated in inflammatory conditions, and their signaling through gp130/LIFR can promote tissue remodeling and fibrosis. Targeting this pathway may offer therapeutic benefits in diseases such as pulmonary fibrosis and rheumatoid arthritis.
Genetic disorders
Mutations in OSMR, which encodes the subunit of the type I OSM receptor, cause familial primary localized cutaneous amyloidosis, a skin disorder characterized by amyloid deposits. Although the type II complex uses LIFR instead of OSMR, the shared gp130 subunit and overlapping signaling pathways suggest that genetic alterations in components of the type II complex could also contribute to related pathologies.
From type II oncostatin-M receptor complex-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| What is the role of gp130 in type II OSM receptor signaling? | IL6ST knockout cell lines (e.g., HEK293, HeLa) |
| How does LIFR mutation affect ligand binding? | Point-mutation knock-in of LIFR in cell lines |
| Can we visualize the receptor complex in live cells? | Tagged knock-in of gp130 or LIFR with fluorescent proteins |
| What are the downstream transcriptional targets? | Overexpression of constitutively active gp130/LIFR followed by RNA-seq |
| Does the complex contribute to cancer cell proliferation? | Knockout of LIFR in breast cancer cell lines |
| How does the receptor complex affect cardiomyocyte survival? | Cardiomyocyte-specific knockout of LIFR in mice |
How to Study the type II oncostatin-M receptor complex Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Cryo-EM | 3D structure of receptor-ligand complexes | Determining assembly and conformational changes |
| RNA-seq | Global gene expression changes | Identifying downstream targets of receptor signaling |
| Proteomics | Protein abundance and modifications | Mapping signaling networks and interactors |
| CRISPR knockout screening | Gene essentiality and synthetic lethality | Discovering regulators of receptor function |
| Flow cytometry | Cell surface receptor expression | Quantifying gp130 and LIFR levels |
| Immunoprecipitation | Protein-protein interactions | Detecting receptor subunit association |
| Luciferase reporter assays | STAT3 transcriptional activity | Measuring pathway activation |
| Live-cell imaging | Receptor trafficking and dynamics | Visualizing internalization and recycling |
Structural biology (cryo-EM)
Cryo-electron microscopy has been used to determine the structures of complete extracellular assemblies of type I and type II OSM receptor complexes, revealing the architecture and ligand-induced conformational changes. These methods are essential for understanding how the receptor subunits interact and how signaling is initiated.
Transcriptomics and proteomics
RNA sequencing (RNA-seq) and mass spectrometry-based proteomics can be used to identify genes and proteins whose expression is regulated by type II OSM receptor signaling. For example, activation of the receptor leads to STAT3-dependent transcriptional programs that can be profiled by RNA-seq.
CRISPR screening
Genome-wide CRISPR knockout screens can identify genes that are essential for type II OSM receptor complex function or that modulate its signaling. Such screens have been used to uncover synthetic heterodimeric gp130:Epo receptor complexes, demonstrating the power of CRISPR for dissecting cytokine receptor signaling.
Imaging and flow cytometry
Fluorescence microscopy and flow cytometry can be used to study the cell surface expression, internalization, and trafficking of the type II OSM receptor complex. Tagged knock-in cell lines expressing fluorescently labeled gp130 or LIFR enable real-time visualization of receptor dynamics.
How CRISPR Can Be Used to Study GO:0140370 type II oncostatin-M receptor complex
Knockout
CRISPR knockout of IL6ST or LIFR can completely abolish type II OSM receptor complex function, allowing researchers to study the specific contributions of each subunit to signaling and downstream biological outcomes. Knockout cell lines are valuable for identifying compensatory pathways and for validating drug targets.
Point Mutation
Point mutations can be introduced into IL6ST or LIFR to mimic disease-associated variants or to disrupt specific interaction interfaces. For example, mutations in the ligand-binding domain of LIFR can be generated to study their effect on LIF binding and receptor activation. Such models are crucial for understanding structure-function relationships.
Knock-in
Knock-in of tagged versions of gp130 or LIFR (e.g., with fluorescent proteins or epitope tags) enables visualization and biochemical isolation of the receptor complex from cells. Knock-in of disease-relevant mutations, such as those found in OSMR, can create isogenic models for studying pathogenesis.
Overexpression
Overexpression of gp130 and LIFR, or of constitutively active mutants, can amplify signaling and reveal downstream effects on cell proliferation, survival, and gene expression. Overexpression models are particularly useful for identifying oncogenic potential and for testing targeted inhibitors.
How EDITGENE Supports type II oncostatin-M receptor complex Research
Researchers studying type II oncostatin-M receptor complex-related genes often need to determine whether a candidate gene is causally involved in receptor signaling, disease progression, or therapeutic response. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this research, from gene knockout to precise point mutations and knock-in models.
Contact EDITGENE today to design your custom CRISPR model for type II oncostatin-M receptor complex research.
Frequently Asked Questions About type II oncostatin-M receptor complex
What is the type II oncostatin-M receptor complex?
The type II oncostatin-M receptor complex (GO:0140370) is a heterodimeric cell surface receptor composed of gp130 and LIFR that binds LIF and related cytokines to activate intracellular signaling.
What genes are involved in the type II oncostatin-M receptor complex?
The core genes are IL6ST (encoding gp130) and LIFR (encoding LIFR). Other related genes include OSMR, LIF, OSM, JAK1, JAK2, STAT3, and SOCS3.
What is the function of the type II oncostatin-M receptor complex?
It mediates signaling by LIF and other cytokines, activating JAK/STAT, MAPK, and PI3K pathways to regulate cell proliferation, differentiation, survival, and inflammation.
How does the type II oncostatin-M receptor complex differ from the type I complex?
The type II complex uses LIFR as the ligand-specific subunit, while the type I complex uses OSMR. They also differ in ligand specificity: type II binds LIF, whereas type I binds OSM but not LIF.
What diseases are associated with the type II oncostatin-M receptor complex?
Dysregulation is linked to cancer, cardiovascular disease, inflammatory and fibrotic diseases, and genetic disorders such as familial primary localized cutaneous amyloidosis (related to OSMR mutations).
How is the type II oncostatin-M receptor complex regulated?
It is regulated by cytokine availability, negative feedback via SOCS3, and phosphatases such as SHP2. Expression of subunits can also be modulated by inflammatory mediators.
What research methods are used to study the type II oncostatin-M receptor complex?
Common methods include cryo-EM for structure, RNA-seq and proteomics for expression profiling, CRISPR screening for gene discovery, and imaging for receptor dynamics.
What CRISPR models are available for studying this receptor complex?
Knockout, point mutation, knock-in (including tagged), and overexpression models can be generated for IL6ST, LIFR, and related genes to dissect their roles in signaling and disease.
Is the type II oncostatin-M receptor complex conserved across species?
It is conserved in humans and rats, but the murine receptor differs in ligand specificity and subunit composition, which is important for preclinical studies.
What is the role of gp130 in the type II oncostatin-M receptor complex?
gp130 is the shared signal-transducing subunit that recruits JAK kinases and activates downstream pathways upon ligand-induced heterodimerization with LIFR.
Conclusion
The type II oncostatin-M receptor complex (GO:0140370) is a critical mediator of cytokine signaling with broad implications for human health and disease. Its heterodimeric structure, composed of gp130 and LIFR, enables specific responses to LIF and related cytokines, activating key pathways such as JAK/STAT, MAPK, and PI3K. Dysregulation of this complex contributes to cancer, cardiovascular disease, and inflammatory disorders, making it an attractive target for therapeutic intervention. Advances in structural biology and CRISPR-based models continue to unravel its mechanisms, offering new opportunities for drug discovery and precision medicine.
References
- 1. Zhou Y et al.. 2024. Structures of complete extracellular assemblies of type I and type II Oncostatin M receptor complexes.. Nat Commun 15(1):9776 PMID: 39532904
- 2. Cichy J et al.. 1998. Regulation of the type II oncostatin M receptor expression in lung-derived epithelial cells.. FEBS Lett 429(3):412-6 PMID: 9662460
- 3. Kubin T et al.. 2022. The Role of Oncostatin M and Its Receptor Complexes in Cardiomyocyte Protection, Regeneration, and Failure.. Int J Mol Sci 23(3) PMID: 35163735
- 4. Akhtar S et al.. 2024. Interleukin-31: The Inflammatory Cytokine Connecting Pruritus and Cancer.. Front Biosci (Landmark Ed) 29(9):312 PMID: 39344323
- 5. Arita K et al.. 2008. Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis.. Am J Hum Genet 82(1):73-80 PMID: 18179886
- 6. Liu J et al.. 1998. Oncostatin M-specific receptor expression and function in regulating cell proliferation of normal and malignant mammary epithelial cells.. Cytokine 10(4):295-302 PMID: 9617575
- 7. Schlei J et al.. 2026. Joined Signatures of Erythropoietin and Interleukin-6 Signaling by Synthetic Heterodimeric gp130:Epo Receptor Complexes.. ACS Synth Biol 15(8):3485-3497 PMID: 42632025
- 8. Drechsler J et al.. 2012. Characterization of the rat oncostatin M receptor complex which resembles the human, but differs from the murine cytokine receptor.. PLoS One 7(8):e43155 PMID: 22937020
