GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand: Dependence Receptor Signaling, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0097192 describes a biological process in which withdrawal of a ligand from a cell surface receptor triggers the extrinsic apoptotic death of a cell.
• This pathway is also known as dependence receptor signaling, because receptors such as DCC, UNC5, and p75NTR actively induce apoptosis when their ligands are absent.
• Ligand-independent extrinsic apoptosis can be induced by viral agents such as myxoma virus in human myeloma cells, showing that the pathway is relevant to cancer therapy.
• The pathway converges on caspase activation and can be modulated by X-linked inhibitor of apoptosis protein (XIAP), which affects apoptosis execution dynamics.
• Network pharmacology studies frequently identify apoptosis-related targets and pathways, including extrinsic apoptotic signaling, as mechanisms of drug action.
• Researchers study this process using knockout, point-mutation, knock-in, and overexpression cell models, combined with CRISPR screening and bioinformatics.
Description
The extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192) is a biological process in which a signal is conveyed from the cell surface to trigger apoptotic death after a ligand is withdrawn from a cell surface receptor. This pathway is distinct from classical extrinsic apoptosis, which is initiated by ligand binding to death receptors; here, the absence of ligand is the trigger. The process is also referred to as dependence receptor signaling, because certain receptors depend on ligand occupancy to suppress their pro-apoptotic activity. Understanding this pathway is important for cancer biology, neurobiology, and drug discovery, as it represents a mechanism by which cells can be eliminated when survival signals are lost. Experimental evidence shows that ligand-independent extrinsic apoptosis can be induced in human myeloma cells by myxoma virus, highlighting its therapeutic potential. Moreover, intracellular signaling dynamics during apoptosis execution are influenced by XIAP, which modulates caspase activity and cell fate. Network pharmacology studies have also identified apoptosis-related pathways, including extrinsic apoptotic signaling, as key mechanisms of action for various compounds. Therefore, GO:0097192 is a critical term for researchers investigating cell death, receptor signaling, and therapeutic strategies.
extrinsic apoptotic signaling pathway in absence of ligand At A Glance
| GO ID | GO:0097192 |
|---|---|
| GO term | extrinsic apoptotic signaling pathway in absence of ligand |
| Ontology | biological_process |
| Synonym | dependence receptor signaling pathway |
| Major function | Triggering apoptosis upon ligand withdrawal from cell surface receptors |
| Pathway start | Withdrawal of a ligand from a cell surface receptor |
| Pathway end | Execution phase of apoptosis is triggered |
| Related process | Extrinsic apoptotic signaling pathway |
What Is GO:0097192?
GO:0097192, extrinsic apoptotic signaling pathway in absence of ligand, is defined as the series of molecular signals in which a signal is conveyed from the cell surface to trigger the apoptotic death of a cell. The pathway starts with withdrawal of a ligand from a cell surface receptor, and ends when the execution phase of apoptosis is triggered. Synonyms include dependence receptor signaling pathway, extrinsic apoptosis in absence of ligand, and extrinsic apoptotic signalling pathway in absence of ligand.
Why Is extrinsic apoptotic signaling pathway in absence of ligand Important in Cell Biology?
GO:0097192 is important because it defines a non-canonical apoptotic mechanism that is critical for development, tissue homeostasis, and cancer suppression. Dependence receptors such as DCC, UNC5, and p75NTR induce apoptosis when their ligands are absent, and this process is essential for eliminating cells that lose survival signals. Dysregulation of this pathway contributes to tumorigenesis, as cancer cells may evade ligand-independent apoptosis. In addition, viral agents like myxoma virus can exploit this pathway to kill myeloma cells, suggesting therapeutic applications. The pathway is also modulated by XIAP, which influences apoptosis execution dynamics and can be targeted to sensitize cells to death. Network pharmacology studies frequently identify apoptosis-related pathways, including extrinsic apoptotic signaling, as mechanisms of drug action, underscoring its broad relevance.
• Provides a mechanism for cell death when survival ligands are withdrawn, critical for development and tissue homeostasis.
• Dependence receptors such as DCC, UNC5, and p75NTR mediate ligand-independent apoptosis and are implicated in cancer and neurodegeneration.
• Ligand-independent extrinsic apoptosis can be induced by myxoma virus in human myeloma cells, offering a therapeutic strategy.
• XIAP modulates apoptosis execution dynamics, affecting the balance between cell survival and death.
• Network pharmacology studies identify apoptosis-related targets and pathways, including extrinsic apoptotic signaling, as mechanisms of drug action.
• The pathway is relevant to cancer therapy, as targeting extrinsic apoptosis signaling can overcome resistance.
• Understanding this pathway aids in the development of CRISPR-based models for gene function studies.
• It is a key term for annotating gene expression and functional genomics data in apoptosis research.
What Happens During extrinsic apoptotic signaling pathway in absence of ligand?
Ligand Withdrawal and Receptor Activation
In simple terms: When a survival ligand disappears, certain receptors on the cell surface become active and send a death signal.
The pathway begins when a ligand is withdrawn from a cell surface receptor, leading to receptor activation or derepression. Dependence receptors, such as DCC, UNC5, and p75NTR, are known to induce apoptosis in the absence of their ligands. This step is critical because it converts a loss of survival signal into a pro-apoptotic signal.
Intracellular Signaling and Caspase Activation
In simple terms: The death signal travels inside the cell and activates caspases, which are enzymes that dismantle the cell.
Following receptor activation, intracellular signaling cascades are initiated, leading to the activation of initiator caspases and subsequently executioner caspases. The dynamics of caspase activation can be influenced by XIAP, which inhibits caspases and modulates apoptosis execution. This step represents the commitment to cell death.
Execution Phase of Apoptosis
In simple terms: The cell undergoes programmed death, breaking down its components.
The pathway ends when the execution phase of apoptosis is triggered, characterized by caspase-mediated cleavage of cellular substrates and DNA fragmentation. This phase is the final common pathway of apoptosis and is regulated by the balance of pro- and anti-apoptotic factors.
Regulation by XIAP and Other Modulators
In simple terms: Proteins like XIAP can put the brakes on apoptosis, affecting whether the cell dies.
XIAP is a key regulator that binds and inhibits caspases, thereby modulating the execution of apoptosis. The presence or absence of XIAP can alter the kinetics of apoptosis execution in response to ligand withdrawal. Other modulators, such as viral proteins, can also influence this pathway.
Key Genes Involved in GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand
The following genes and proteins are central to the extrinsic apoptotic signaling pathway in absence of ligand, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| DCC | Dependence receptor that induces apoptosis in absence of netrin-1 | Implicated in cancer and neurodevelopment |
| UNC5 | Dependence receptor family member that triggers apoptosis without netrin-1 | Studied in cancer and neuronal survival |
| p75NTR | Neurotrophin receptor that mediates apoptosis in absence of neurotrophins | Relevant to neurodegeneration and cancer |
| CASP8 | Initiator caspase in extrinsic apoptosis | Key effector of ligand-independent apoptosis |
| CASP3 | Executioner caspase | Mediates apoptosis execution |
| CASP7 | Executioner caspase | Contributes to apoptosis execution |
| XIAP | Inhibitor of apoptosis protein | Modulates caspase activity and apoptosis dynamics |
| FADD | Adaptor protein in death receptor signaling | Links receptors to caspase activation |
| TNFRSF10A | Death receptor | Can mediate extrinsic apoptosis |
| TNFRSF10B | Death receptor | Can mediate extrinsic apoptosis |
| BCL2 | Anti-apoptotic protein | Regulates mitochondrial apoptosis |
| BAX | Pro-apoptotic protein | Promotes mitochondrial outer membrane permeabilization |
| BAK | Pro-apoptotic protein | Promotes mitochondrial outer membrane permeabilization |
| APAF1 | Apoptosome component | Activates caspase-9 |
| CYCS | Cytochrome c | Released from mitochondria to activate caspases |
| DIABLO | IAP antagonist | Promotes caspase activation |
| BIRC5 | Survivin, IAP family member | Inhibits caspases |
How Is extrinsic apoptotic signaling pathway in absence of ligand Regulated?
The extrinsic apoptotic signaling pathway in absence of ligand is regulated at multiple levels. XIAP directly inhibits caspases, thereby modulating the threshold for apoptosis execution. Dependence receptors such as DCC, UNC5, and p75NTR are regulated by ligand availability; in the absence of ligands, they adopt pro-apoptotic conformations or interact with co-receptors. Viral proteins can also modulate this pathway; for example, myxoma virus induces ligand-independent extrinsic apoptosis in myeloma cells. Additionally, network pharmacology studies have identified apoptosis-related pathways as targets of various compounds, suggesting that small molecules can regulate this process.
extrinsic apoptotic signaling pathway in absence of ligand and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| DCC | Colorectal cancer, neuronal apoptosis | Knockout and point-mutation cell models |
| UNC5 | Cancer, neurodevelopment | Knock-in and overexpression models |
| p75NTR | Neurodegeneration, cancer | Knockout and tagged knock-in models |
| XIAP | Cancer, apoptosis resistance | Point-mutation and knockout models |
| CASP8 | Cancer, immunodeficiency | Knockout and overexpression models |
Cancer
Dependence receptors such as DCC and UNC5 are frequently downregulated or mutated in cancers, allowing cells to evade ligand-independent apoptosis. Targeting the extrinsic apoptosis pathway is a therapeutic strategy for cancer. Myxoma virus induces ligand-independent extrinsic apoptosis in human myeloma cells, suggesting oncolytic virotherapy potential.
Neurodegeneration
p75NTR mediates apoptosis in the absence of neurotrophins, and dysregulation of this pathway contributes to neuronal loss in neurodegenerative diseases. Understanding ligand-independent apoptosis may inform neuroprotective strategies.
Autoimmune and Inflammatory Diseases
Defective apoptosis can lead to autoimmunity, while excessive apoptosis contributes to tissue damage. The extrinsic apoptotic pathway in absence of ligand is implicated in these processes. Network pharmacology studies have identified apoptosis-related pathways as mechanisms of anti-inflammatory compounds.
From extrinsic apoptotic signaling pathway in absence of ligand-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X mediate ligand-independent apoptosis? | Knockout cell model |
| Does a specific mutation in gene X alter apoptosis sensitivity? | Point-mutation knock-in model |
| Does overexpression of gene X protect from apoptosis? | Overexpression cell model |
| Where is protein X localized during apoptosis? | Tagged knock-in model |
| Which genes are essential for ligand-independent apoptosis? | CRISPR library screening |
| What are the transcriptomic changes during apoptosis? | RNA-seq and bioinformatics |
How to Study the extrinsic apoptotic signaling pathway in absence of ligand Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screening | Gene essentiality | Identify regulators of ligand-independent apoptosis |
| RNA-seq | Transcriptome changes | Discover gene expression signatures |
| Proteomics | Protein abundance and modifications | Map signaling pathways |
| Live-cell imaging | Caspase activity and cell death | Monitor apoptosis dynamics |
| Flow cytometry | Apoptosis markers | Quantify cell death |
| Western blot | Protein cleavage and expression | Validate caspase activation |
| Network pharmacology | Drug-target interactions | Identify apoptosis-modulating compounds |
CRISPR Knockout Screening
CRISPR knockout screens can identify genes essential for ligand-independent apoptosis. By transducing cells with a genome-wide sgRNA library and inducing ligand withdrawal, researchers can select for cells that survive or die, revealing candidate regulators.
RNA Sequencing and Transcriptomics
RNA-seq measures global gene expression changes during ligand-independent apoptosis. This method can identify pathways and gene signatures associated with the process.
Proteomics and Phosphoproteomics
Mass spectrometry-based proteomics can quantify protein abundance and post-translational modifications during apoptosis, revealing signaling dynamics.
Live-Cell Imaging
Fluorescent reporters for caspases and mitochondrial integrity allow real-time monitoring of apoptosis execution in response to ligand withdrawal.
How CRISPR Can Be Used to Study GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand
Knockout
CRISPR knockout of genes such as DCC, UNC5, or p75NTR can abolish ligand-independent apoptosis, confirming their essential roles. Knockout models are used to study loss-of-function phenotypes in cancer and neuronal cells.
Point Mutation
Point mutations in caspase cleavage sites or receptor domains can dissect signaling mechanisms. For example, mutating caspase-8 cleavage sites in dependence receptors can prevent apoptosis induction.
Knock-in
Knock-in of tagged versions of receptors or caspases allows visualization and purification of protein complexes during apoptosis. This approach helps track protein localization and interactions.
Overexpression
Overexpression of anti-apoptotic proteins like XIAP or BCL2 can protect cells from ligand-independent apoptosis, while overexpression of pro-apoptotic factors sensitizes cells. Overexpression models are useful for gain-of-function studies.
How EDITGENE Supports extrinsic apoptotic signaling pathway in absence of ligand Research
Researchers studying extrinsic apoptotic signaling pathway in absence of ligand-related genes often need to determine whether a candidate gene is causally involved in ligand-independent cell death. EDITGENE provides comprehensive CRISPR-based services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for extrinsic apoptotic signaling pathway in absence of ligand research.
Frequently Asked Questions About extrinsic apoptotic signaling pathway in absence of ligand
What is GO:0097192?
GO:0097192 is the Gene Ontology term for extrinsic apoptotic signaling pathway in absence of ligand, a process where ligand withdrawal from a cell surface receptor triggers apoptosis.
What genes are involved in extrinsic apoptotic signaling pathway in absence of ligand?
Key genes include DCC, UNC5, p75NTR, CASP8, CASP3, XIAP, and FADD.
What is dependence receptor signaling?
Dependence receptor signaling is a synonym for GO:0097192, where receptors such as DCC and UNC5 induce apoptosis when their ligands are absent.
How is extrinsic apoptotic signaling pathway in absence of ligand studied?
It is studied using CRISPR knockout screens, RNA-seq, proteomics, live-cell imaging, and network pharmacology.
What diseases are associated with GO:0097192?
It is associated with cancer, neurodegeneration, and autoimmune diseases.
Can viruses induce ligand-independent apoptosis?
Yes, myxoma virus induces ligand-independent extrinsic apoptosis in human myeloma cells.
What is the role of XIAP in this pathway?
XIAP inhibits caspases and modulates apoptosis execution dynamics.
What are the synonyms for GO:0097192?
Synonyms include dependence receptor signaling pathway, extrinsic apoptosis in absence of ligand, and extrinsic apoptotic signalling pathway in absence of ligand.
How can CRISPR help study GO:0097192?
CRISPR knockout, point mutation, knock-in, and overexpression models can dissect gene function in this pathway.
What services does EDITGENE offer for apoptosis research?
EDITGENE offers knockout, point mutation, knock-in, overexpression cell models, CRISPR library screening, and bioinformatics services.
Conclusion
GO:0097192, extrinsic apoptotic signaling pathway in absence of ligand, is a fundamental biological process that links ligand withdrawal to programmed cell death. Its dysregulation contributes to cancer, neurodegeneration, and other diseases. Studying this pathway using CRISPR-based models and bioinformatics can reveal new therapeutic targets. EDITGENE provides the tools and services to accelerate this research.
References
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- 4. O'Connor CL et al.. 2008. Intracellular signaling dynamics during apoptosis execution in the presence or absence of X-linked-inhibitor-of-apoptosis-protein.. Biochim Biophys Acta 1783(10):1903-13 PMID: 18590777
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