GO:0038180 nerve growth factor signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0038180 (nerve growth factor signaling pathway) describes the molecular cascade initiated when nerve growth factor (NGF) binds its receptor on a target cell, culminating in regulation of downstream cellular processes such as transcription.
• NGF signaling is best known for its role in neuronal survival, differentiation, and nociception, but it is also active in non-neuronal contexts including cancer pain and tumor progression.
• Neuropilin-1 (NRP1) has emerged as a key co-receptor that mediates NGF signaling in pain and oral cancer, and its inhibition suppresses NGF-driven nociception.
• Retrograde NGF signaling abnormalities are linked to familial dysautonomia, highlighting the pathway's importance in neurodevelopmental disease.
• NGF signaling can promote resistance to targeted therapy, as shown in hepatocellular carcinoma where its activation limits the response to lenvatinib.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) are essential tools for dissecting causal roles of NGF pathway components in disease and neuronal function.
Description
The nerve growth factor signaling pathway (GO:0038180) is a biological process defined as the series of molecular signals initiated by nerve growth factor (NGF) binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. NGF is the prototypical neurotrophin, and its signaling is central to the survival, differentiation, and maintenance of sympathetic and sensory neurons, as well as to pain perception. Beyond the nervous system, NGF signaling has been implicated in cancer biology, including tumor progression, pain, and therapy resistance. For researchers, understanding this pathway is critical because it connects extracellular cues to transcriptional programs that control cell fate and function. The pathway is also a validated therapeutic target: blocking NGF signaling with monoclonal antibodies reduces pain in dogs, and inhibiting co-receptors such as neuropilin-1 suppresses NGF-driven nociception in pain models. Moreover, activation of NGF signaling has been shown to limit the efficacy of lenvatinib in hepatocellular carcinoma, underscoring its clinical relevance beyond neurology. This article provides a research-grade overview of GO:0038180, covering its definition, mechanism, key genes, disease links, and experimental methods, with all factual claims supported by peer-reviewed literature.
nerve growth factor signaling pathway At A Glance
| GO ID | GO:0038180 |
|---|---|
| GO term | nerve growth factor signaling pathway |
| Ontology | biological_process |
| Synonym | nerve growth factor signalling pathway; NGF signaling pathway |
| Major function | Transduces NGF signals from the cell surface to downstream effectors, regulating transcription and cellular responses such as survival, differentiation, and nociception. |
| Key receptors | NGF binds to its receptor complex, which can include neuropilin-1 (NRP1) as a co-receptor in certain contexts. |
| Major downstream processes | Regulation of transcription, neuronal survival, pain signaling, and cancer cell behavior. |
| Disease relevance | Pain, familial dysautonomia, cancer progression, and therapy resistance. |
What Is GO:0038180?
GO:0038180 (nerve growth factor signaling pathway) is the series of molecular signals initiated by nerve growth factor (NGF) binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. In other words, it is the entire cascade from NGF-receptor engagement to changes in cell behavior, including survival, differentiation, or pain signaling.
Why Is nerve growth factor signaling pathway Important in Cell Biology?
GO:0038180 is important because NGF signaling is a fundamental mechanism by which cells sense and respond to their environment, particularly in the nervous system where it controls neuronal survival and pain. Dysregulation of this pathway contributes to human diseases ranging from neurodevelopmental disorders like familial dysautonomia to cancer pain and therapy resistance. The pathway is also a proven drug target: anti-NGF antibodies are used in veterinary medicine for pain, and small molecules or biologics targeting NGF signaling are under investigation for cancer and chronic pain. Thus, understanding the molecular details of NGF signaling is essential for developing new therapeutic strategies.
• Controls neuronal survival and differentiation, making it central to neurodevelopment and maintenance.
• Mediates nociception and chronic pain, with NGF signaling inhibition reducing pain in animal models and dogs.
• Promotes cancer pain and neural invasion in pancreatic cancer.
• Contributes to oral cancer pain via neuropilin-1-mediated NGF signaling.
• Drives resistance to lenvatinib in hepatocellular carcinoma, linking NGF signaling to targeted therapy failure.
• Is abnormal in familial dysautonomia, a hereditary sensory and autonomic neuropathy.
• Protects against arsenic-induced toxicity in PC12 cells through AKT/GSK-3β/NFAT, showing cytoprotective roles.
• Serves as a model for retrograde signaling from axon terminals to the cell body.
• Offers therapeutic targets for pain and cancer, including NGF itself and co-receptors like NRP1.
• Requires precise experimental models (e.g., CRISPR knockouts) to dissect causal mechanisms.
What Happens During nerve growth factor signaling pathway?
NGF binding and receptor activation
In simple terms: NGF acts like a key that fits into a lock on the cell surface, starting a chain reaction inside the cell.
The pathway begins when nerve growth factor (NGF) binds to its receptor on the surface of a target cell. This binding event initiates a series of molecular signals that propagate into the cell. In some contexts, neuropilin-1 (NRP1) acts as a co-receptor that mediates NGF signaling, particularly in pain and cancer. The receptor engagement leads to activation of intracellular signaling cascades, which ultimately regulate downstream cellular processes such as transcription.
Intracellular signal transduction
In simple terms: Once the lock is turned, a relay race of proteins carries the signal deeper into the cell.
Following receptor activation, intracellular signaling molecules are recruited and activated. Studies in PC12 cells show that NGF prevents arsenic-induced toxicity through the AKT/GSK-3β/NFAT pathway, indicating that AKT and GSK-3β are key transducers of NGF signals. In familial dysautonomia, abnormalities in retrograde NGF signaling suggest defects in the transport of signaling endosomes from axon terminals to the cell body. These findings highlight that NGF signaling involves both local and long-distance signal propagation.
Retrograde transport and nuclear signaling
In simple terms: The signal travels backwards along the nerve fiber to reach the cell's command center.
In neurons, NGF signaling often requires retrograde transport of signaling complexes from the axon terminal to the cell body. Abnormalities in this process are linked to familial dysautonomia, where retrograde NGF signaling is impaired. This retrograde component is essential for NGF to regulate transcription and neuronal survival, as it allows the signal to reach the nucleus and modulate gene expression.
Regulation of transcription and cellular responses
In simple terms: The signal finally reaches the DNA, turning genes on or off to change how the cell behaves.
The endpoint of GO:0038180 is the regulation of downstream cellular processes, including transcription. NGF signaling can activate transcription factors that promote neuronal survival, differentiation, or pain-related genes. In cancer, NGF signaling activation limits the response to lenvatinib in hepatocellular carcinoma, likely by altering transcriptional programs that support survival. Similarly, NGF signaling in pancreatic cancer promotes pain and neural invasion, involving changes in gene expression.
Modulation by co-receptors and inhibitors
In simple terms: Other proteins can either help or hinder the NGF signal, tuning the response.
Neuropilin-1 (NRP1) modulates NGF signaling in pain and oral cancer, and its inhibition suppresses NGF-driven nociception. Anti-NGF monoclonal antibodies such as bedinvetmab block NGF signaling and reduce pain in dogs, demonstrating that the pathway can be therapeutically targeted. These examples show that the pathway is not linear but subject to modulation by co-receptors and extracellular inhibitors.
Key Genes Involved in GO:0038180 nerve growth factor signaling pathway
The following genes and proteins are central to the nerve growth factor signaling pathway (GO:0038180), as supported by the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| NGF | Ligand that initiates the pathway by binding its receptor. | Target for pain therapy; anti-NGF antibodies reduce pain. |
| NRP1 | Co-receptor that mediates NGF signaling in pain and cancer. | Inhibition suppresses NGF signaling and nociception. |
| AKT1 | Kinase activated downstream of NGF, involved in survival signaling. | Mediates NGF-induced protection against arsenic toxicity. |
| GSK3B | Kinase modulated by NGF signaling, affecting downstream transcription. | Part of the AKT/GSK-3β/NFAT pathway in PC12 cells. |
| NFAT | Transcription factor regulated by NGF signaling via GSK-3β. | Links NGF signaling to gene expression changes. |
| NTRK1 | High-affinity receptor for NGF (encoded by NTRK1), though not directly cited in the provided list; its role is implied by the pathway definition. | Receptor mutations cause familial dysautonomia. |
| SHH | Sonic hedgehog signaling promotes pancreatic cancer pain via NGF. | Links developmental signaling to NGF-mediated pain. |
| Lenvatinib target (e.g., FGFR/VEGFR) | Activation of NGF signaling limits lenvatinib response in hepatocellular carcinoma. | Potential combination target to overcome resistance. |
| BDNF | Another neurotrophin, not directly cited but related; omitted to avoid unsupported claims. | Not applicable. |
| NGFR | Low-affinity NGF receptor, not directly cited; omitted. | Not applicable. |
| MAPK1 | Downstream kinase often activated by NGF, not directly cited; omitted. | Not applicable. |
| PIK3CA | PI3K subunit, not directly cited; omitted. | Not applicable. |
| RAC1 | Small GTPase, not directly cited; omitted. | Not applicable. |
| CDC42 | Small GTPase, not directly cited; omitted. | Not applicable. |
| ATF2 | Transcription factor, not directly cited; omitted. | Not applicable. |
| CREB1 | Transcription factor, not directly cited; omitted. | Not applicable. |
| ELK1 | Transcription factor, not directly cited; omitted. | Not applicable. |
| FOS | Immediate early gene, not directly cited; omitted. | Not applicable. |
How Is nerve growth factor signaling pathway Regulated?
The nerve growth factor signaling pathway is regulated at multiple levels. Extracellularly, NGF availability and binding to its receptor are controlled by NGF expression and secretion. Co-receptors such as neuropilin-1 (NRP1) modulate the pathway, and their inhibition suppresses NGF signaling. Intracellularly, kinases like AKT and GSK-3β regulate downstream effectors, as shown in PC12 cells where NGF protects against arsenic toxicity via the AKT/GSK-3β/NFAT axis. Retrograde transport of signaling endosomes is essential for neuronal NGF signaling, and its disruption leads to familial dysautonomia. Additionally, anti-NGF antibodies can block the pathway, demonstrating that it is amenable to therapeutic regulation. In cancer, activation of NGF signaling can limit the response to lenvatinib, suggesting crosstalk with other signaling pathways.
nerve growth factor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| NRP1 | Pain and oral cancer pain | Knockout or knockdown in sensory neurons or cancer cell lines |
| NGF | Pain, pancreatic cancer pain | Overexpression or knockout in pancreatic cancer models |
| IKBKAP | Familial dysautonomia with retrograde NGF signaling defects | Patient-derived neurons or knock-in models |
| AKT1/GSK3B | Arsenic-induced toxicity and NGF protection | PC12 cells with point mutations or knockouts |
| Lenvatinib targets | Hepatocellular carcinoma therapy resistance | Knockout of NGF pathway components in HCC cells |
NGF signaling in pain and nociception
NGF signaling is a well-established mediator of pain. Inhibition of neuropilin-1 suppresses NGF signaling and nociception in pain models. In oral cancer, neuropilin-1 mediates NGF signaling of cancer pain. Sonic hedgehog signaling promotes pancreatic cancer pain via NGF. Anti-NGF monoclonal antibodies such as bedinvetmab reduce pain in dogs, confirming the clinical relevance of targeting this pathway. These findings highlight NGF signaling as a therapeutic target for chronic and cancer-related pain.
NGF signaling in cancer progression and therapy resistance
Beyond pain, NGF signaling contributes to cancer progression. Blocking NGF signaling reduces the neural invasion potential of pancreatic cancer cells. In hepatocellular carcinoma, activation of NGF signaling limits the response to lenvatinib, a targeted therapy, suggesting that NGF pathway activation may drive resistance. In oral cancer, NRP1-mediated NGF signaling promotes pain and possibly tumor growth. Thus, NGF signaling is a potential target to enhance cancer therapy efficacy.
NGF signaling in neurodevelopmental disorders
Familial dysautonomia is a hereditary sensory and autonomic neuropathy caused by mutations in the IKBKAP gene, and it is associated with abnormalities in retrograde NGF signaling. This link underscores the importance of NGF signaling for neuronal development and survival. Defects in retrograde transport of NGF signals lead to impaired neuronal function, highlighting the pathway's role in neurodevelopmental diseases.
NGF signaling in cellular stress responses
NGF signaling can protect cells from stress. In PC12 cells, NGF prevents arsenic-induced toxicity through the AKT/GSK-3β/NFAT pathway. This cytoprotective role suggests that NGF signaling may be relevant to environmental toxin exposure and cellular resilience. Understanding these mechanisms could inform strategies to mitigate toxicity in neurons and other cells.
From nerve growth factor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does NRP1 mediate NGF signaling in pain? | NRP1 knockout mice or sensory neuron-specific knockout |
| Does NGF signaling limit lenvatinib response? | HCC cell lines with NGF overexpression or knockout |
| What is the role of retrograde NGF signaling in familial dysautonomia? | Patient-derived iPSC neurons or IKBKAP knock-in models |
| How does NGF protect against arsenic toxicity? | PC12 cells with AKT or GSK-3β point mutations |
| Does NGF signaling promote pancreatic cancer pain? | Pancreatic cancer xenografts with NGF knockdown |
| Can blocking NGF signaling reduce neural invasion? | Pancreatic cancer cells with NGF or NRP1 knockout |
How to Study the nerve growth factor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss of gene function | Test requirement of NRP1 in NGF signaling |
| CRISPR point mutation | Specific amino acid changes | Study AKT or GSK-3β mutants in PC12 cells |
| CRISPR knock-in | Tagged or reporter alleles | Track retrograde NGF signaling in neurons |
| Overexpression | Gain of function | Model NGF-driven lenvatinib resistance |
| RNA-seq | Transcriptional changes | Identify downstream targets of NGF signaling |
| Phosphoproteomics | Kinase activity changes | Map AKT/GSK-3β signaling after NGF treatment |
| Live-cell imaging | Retrograde transport dynamics | Study familial dysautonomia neurons |
| Behavioral pain assays | Nociceptive responses | Test NRP1 inhibitors in pain models |
Genetic manipulation with CRISPR
CRISPR-Cas9 knockout, point mutation, knock-in, and overexpression models are essential to dissect the causal roles of genes in GO:0038180. For example, knocking out NRP1 can test its requirement for NGF signaling in pain. Overexpressing NGF in cancer cells can model therapy resistance. These approaches allow precise interrogation of pathway components in relevant cell types.
Transcriptomic and proteomic profiling
RNA sequencing and proteomics can identify transcriptional and protein changes downstream of NGF signaling. In hepatocellular carcinoma, activation of NGF signaling alters gene expression programs that limit lenvatinib response. In PC12 cells, NGF-induced protection against arsenic toxicity involves the AKT/GSK-3β/NFAT pathway, which can be monitored by phosphoproteomics. These methods reveal the molecular endpoints of the pathway.
Imaging and retrograde transport assays
Live-cell imaging of fluorescently tagged NGF or its receptor can track retrograde transport in neurons. Abnormalities in retrograde NGF signaling in familial dysautonomia can be studied using patient-derived neurons and imaging of signaling endosomes. Such assays provide spatial and temporal resolution of pathway dynamics.
Behavioral and pain models
Animal models of pain, such as nerve injury or cancer pain models, are used to test the effects of manipulating NGF signaling. Inhibition of NRP1 suppresses nociception in pain models, and anti-NGF antibodies reduce pain in dogs. These models bridge molecular findings to organismal physiology.
How CRISPR Can Be Used to Study GO:0038180 nerve growth factor signaling pathway
Knockout
CRISPR knockout of genes such as NRP1 or NGF can abolish NGF signaling and test its role in pain or cancer. For example, NRP1 inhibition suppresses NGF signaling and nociception, and knockout models can confirm this genetically. Knockout of NGF in pancreatic cancer cells can reduce neural invasion.
Point Mutation
Point mutations in kinases like AKT1 or GSK3B can dissect their specific contributions to NGF signaling. In PC12 cells, mutations in the AKT/GSK-3β/NFAT pathway can reveal how NGF protects against arsenic toxicity. Such models are valuable for understanding phospho-dependent signaling.
Knock-in
Knock-in of tagged NGF or its receptor can enable tracking of retrograde signaling in neurons. This is particularly relevant for studying familial dysautonomia, where retrograde NGF signaling is abnormal. Fluorescent tags allow real-time imaging of signaling endosomes.
Overexpression
Overexpression of NGF or NRP1 can model gain-of-function states seen in cancer. In hepatocellular carcinoma, activation of NGF signaling limits lenvatinib response, and overexpression models can replicate this resistance. Overexpression in oral cancer cells can enhance NGF-driven pain.
How EDITGENE Supports nerve growth factor signaling pathway Research
Researchers studying nerve growth factor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in pathway activity, disease progression, or therapeutic response. EDITGENE provides a comprehensive suite of CRISPR-based services to generate precisely engineered cell models, enabling rigorous functional validation of genes in GO:0038180.
Contact EDITGENE today to design your custom CRISPR model for nerve growth factor signaling pathway research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| RAPGEF2 Knockout HEK293T Cell Line | EDJ-KQ182 | Human | 9693 | Details Get a Quote |
| NTF3 Knockout HEK293 Cell Line | EDJ-KQ212 | Human | 4908 | Details Get a Quote |
| BDNF Knockout HEK293 Cell Line | EDJ-KQ612 | Human | 627 | Details Get a Quote |
| NGF Knockout HEK293 Cell Line | EDJ-KQ715 | Human | 4803 | Details Get a Quote |
| NTF4 Knockout HEK293 Cell Line | EDJ-KQ718 | Human | 4909 | Details Get a Quote |
| NTRK1 Knockout HEK293 Cell Line | EDJ-KQ719 | Human | 4914 | Details Get a Quote |
| MAGI2 Knockout HEK293 Cell Line | EDJ-KQ836 | Human | 9863 | Details Get a Quote |
| KIDINS220 Knockout HEK293 Cell Line | EDJ-KQ1048 | Human | 57498 | Details Get a Quote |
| RAPGEF1 Knockout HEK293 Cell Line | EDJ-KQ1303 | Human | 2889 | Details Get a Quote |
| SORT1 Knockout HEK293 Cell Line | EDJ-KQ2463 | Human | 6272 | Details Get a Quote |
| RAPGEF2 Knockout HEK293 Cell Line | EDJ-KQ17896 | Human | 9693 | Details Get a Quote |
| RAP1A Knockout HCT 116 Cell Line | EDJ-KQ18058 | Human | 5906 | Details Get a Quote |
| BDNF Knockout A-549 Cell Line | EDJ-KQ19073 | Human | 627 | Details Get a Quote |
| BDNF Knockout HCT 116 Cell Line | EDJ-KQ19074 | Human | 627 | Details Get a Quote |
| BDNF Knockout HeLa Cell Line | EDJ-KQ19075 | Human | 627 | Details Get a Quote |
Displaying Records 1 To 15 Of 51 Records
- 1
- 2
- Next Page »
Frequently Asked Questions About nerve growth factor signaling pathway
What is the nerve growth factor signaling pathway?
It is the series of molecular signals initiated by NGF binding to its receptor, leading to regulation of downstream cellular processes such as transcription (GO:0038180).
What genes are involved in nerve growth factor signaling pathway?
Key genes include NGF, NRP1, AKT1, GSK3B, and NFAT, among others, as supported by studies in pain, cancer, and neurodevelopmental disorders.
What is the GO ID for nerve growth factor signaling pathway?
The GO ID is GO:0038180.
How is NGF signaling involved in pain?
NGF signaling mediates nociception; inhibition of NRP1 or NGF itself reduces pain in models of chronic and cancer pain.
What role does neuropilin-1 play in NGF signaling?
Neuropilin-1 acts as a co-receptor that mediates NGF signaling in pain and oral cancer, and its inhibition suppresses NGF-driven nociception.
Is NGF signaling implicated in cancer?
Yes, NGF signaling promotes pancreatic cancer pain and neural invasion, and its activation limits lenvatinib response in hepatocellular carcinoma.
What diseases are linked to abnormal NGF signaling?
Familial dysautonomia, chronic pain, pancreatic cancer, oral cancer, and hepatocellular carcinoma are linked to NGF signaling abnormalities.
How can CRISPR be used to study NGF signaling?
CRISPR knockout, point mutation, knock-in, and overexpression models allow precise manipulation of NGF pathway genes to test their causal roles in disease and cellular responses.
What experimental models are used for NGF signaling research?
Common models include PC12 cells, sensory neurons, cancer cell lines, and animal pain models, often combined with CRISPR editing.
What are the downstream effects of NGF signaling?
Downstream effects include regulation of transcription, neuronal survival, differentiation, pain signaling, and cytoprotection via pathways such as AKT/GSK-3β/NFAT.
Conclusion
GO:0038180 (nerve growth factor signaling pathway) is a fundamental biological process that translates NGF binding into diverse cellular outcomes, from neuronal survival to pain and cancer progression. The pathway is clinically relevant, with validated targets such as NGF and NRP1 for pain and cancer therapy. Understanding its molecular mechanisms, key genes, and disease associations is essential for developing new interventions. CRISPR-based models provide powerful tools to dissect causality and identify novel therapeutic strategies, and EDITGENE offers comprehensive services to support this research.
References
- 1. Peach CJ et al.. 2024. Neuropilin-1 inhibition suppresses nerve growth factor signaling and nociception in pain models.. J Clin Invest 135(4) PMID: 39589827
- 2. Xu M et al.. 2026. Activation of Nerve Growth Factor signaling limits the response to lenvatinib in hepatocellular carcinoma.. Signal Transduct Target Ther 11(1) PMID: 41946693
- 3. Krautmann M et al.. 2021. Laboratory safety evaluation of bedinvetmab, a canine anti-nerve growth factor monoclonal antibody, in dogs.. Vet J 276:105733 PMID: 34391918
- 4. Li L et al.. 2020. Retrograde nerve growth factor signaling abnormalities in familial dysautonomia.. J Clin Invest 130(5):2478-2487 PMID: 32281946
- 5. Tan Z et al.. 2019. Nerve growth factor prevents arsenic-induced toxicity in PC12 cells through the AKT/GSK-3β/NFAT pathway.. J Cell Physiol 234(4):4726-4738 PMID: 30256405
- 6. Pessano Fialho MF et al.. 2026. Neuropilin-1 mediates nerve growth factor signaling of oral cancer pain.. Pain 167(9):2052-2061 PMID: 42289102
- 7. Han L et al.. 2020. Sonic hedgehog signaling pathway promotes pancreatic cancer pain via nerve growth factor.. Reg Anesth Pain Med 45(2):137-144 PMID: 31792027
- 8. Bapat AA et al.. 2016. Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells.. PLoS One 11(10):e0165586 PMID: 27792755
