GO:0017154 semaphorin receptor activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0017154 semaphorin receptor activity is a molecular function defined as combining with a semaphorin and transmitting the signal across the membrane to initiate a change in cell activity.
• Semaphorin receptors include plexins, neuropilins, and CD72, which mediate axon guidance, immune regulation, and cancer progression.
• Dysregulated semaphorin signaling contributes to cancer metastasis, liver fibrosis, lung fibrosis, neovascular age-related macular degeneration, and pancreatic perineural invasion.
• Key semaphorin-receptor pairs include SEMA3C-NRP2, SEMA4D-PlexinB1, SEMA3E-PlexinD1, and SEMA6D-PlexinA1.
• CRISPR knockout, point mutation, knock-in, and overexpression models are essential to dissect semaphorin receptor function in disease.
• EDITGENE provides custom cell models and CRISPR library screening to accelerate semaphorin receptor research.
Description
Semaphorin receptor activity (GO:0017154) is a molecular function that enables a cell to bind a semaphorin ligand and convert that binding event into an intracellular signal, thereby changing cell behavior. Semaphorins are a large family of secreted and membrane-bound proteins originally identified as axon guidance cues, but now recognized as critical regulators of immunity, angiogenesis, and tumor progression. The receptors that mediate these effects include plexins, neuropilins, and CD72, which together form a versatile signaling hub. Understanding semaphorin receptor activity is therefore central to developmental biology, neurobiology, and cancer research. In cancer, semaphorin receptors such as NRP2 and PlexinB1 are hijacked to promote metastasis, fibrosis, and immune evasion. For example, cancer-associated fibroblast-derived SEMA3C signals through NRP2 to activate MAPK and drive colorectal cancer liver metastasis. Similarly, the SEMA4D-PlexinB1 axis activates pericytes in neovascular age-related macular degeneration, and SEMA3E-PlexinD1 signaling promotes lung fibrosis through ErbB2. These findings highlight semaphorin receptor activity as a therapeutic target and a rich area for CRISPR-based functional genomics. This article provides a research-grade overview of GO:0017154, covering its definition, molecular mechanism, key genes, disease relevance, and state-of-the-art methods including CRISPR screening and cell model generation. All statements are grounded in published literature to support reproducibility and generative-AI retrieval.
semaphorin receptor activity At A Glance
| GO ID | GO:0017154 |
|---|---|
| GO term | semaphorin receptor activity |
| Ontology | molecular_function |
| Synonym | none |
| Major function | Binding semaphorins and transmitting signals across the membrane to initiate changes in cell activity |
| Major receptor families | Plexins, neuropilins, CD72 |
| Key ligands | Semaphorins (e.g., SEMA3C, SEMA4D, SEMA3E, SEMA6D) |
| Associated processes | Axon guidance, immune regulation, angiogenesis, cancer metastasis, fibrosis |
| Disease relevance | Cancer, liver fibrosis, lung fibrosis, neovascular AMD, pancreatic perineural invasion |
What Is GO:0017154?
According to the Gene Ontology, semaphorin receptor activity (GO:0017154) is defined as combining with a semaphorin and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity. In simpler terms, it is the function of a receptor protein that binds a semaphorin ligand outside the cell and relays that information inside the cell to trigger a response. This activity is distinct from merely binding a semaphorin; it requires signal transduction across the membrane.
Why Is semaphorin receptor activity Important in Cell Biology?
Semaphorin receptor activity is important because it governs fundamental processes such as axon guidance, immune cell activation, and vascular patterning, and its dysregulation is increasingly linked to major human diseases including cancer, fibrosis, and neurodegeneration. Targeting these receptors with CRISPR-based models can reveal causal mechanisms and identify new therapeutic strategies.
• Regulates axon guidance and neural circuit formation.
• Controls immune cell activation and inflammatory responses.
• Promotes cancer metastasis via NRP2 and MAPK signaling.
• Drives liver fibrosis through SEMA3C.
• Mediates lung fibrosis via SEMA3E-PlexinD1-ErbB2.
• Activates pericytes in neovascular age-related macular degeneration.
• Supports perineural invasion in pancreatic cancer.
• Provides targets for CRISPR knockout and knock-in studies.
• Enables high-throughput screening for receptor modulators.
• Links developmental biology to adult disease mechanisms.
What Happens During semaphorin receptor activity?
Ligand binding and receptor complex formation
In simple terms: A semaphorin molecule binds to its receptor on the cell surface, often with a co-receptor, to start the signaling process.
Semaphorin receptor activity begins when a secreted or membrane-bound semaphorin binds to a receptor complex. For example, SEMA3C binds to NRP2 to form a signaling-competent complex that activates MAPK in colorectal cancer cells. Similarly, SEMA4D binds to PlexinB1 on pericytes, and SEMA3E engages PlexinD1 on fibroblasts. This binding event is the first step in transmitting the signal across the membrane.
Signal transduction across the membrane
In simple terms: The receptor changes shape and passes the signal to the inside of the cell.
Upon ligand binding, semaphorin receptors such as plexins undergo conformational changes that activate their intracellular domains. Plexins can directly transduce signals through their GTPase-activating protein (GAP) domains or by recruiting adaptor proteins. This step is essential for converting the extracellular semaphorin cue into an intracellular biochemical signal.
Activation of downstream pathways
In simple terms: The signal triggers a cascade of molecular events inside the cell.
Semaphorin receptor activity leads to activation of diverse downstream pathways, including MAPK, ErbB2, and Rho GTPases. For instance, SEMA3C-NRP2 signaling activates MAPK to promote liver metastasis, while SEMA3E-PlexinD1 activates ErbB2 in lung fibrosis. These pathways ultimately alter gene expression, cytoskeletal dynamics, and cell behavior.
Cellular responses and physiological outcomes
In simple terms: The cell changes its behavior, such as moving, growing, or activating immune responses.
The downstream signaling triggered by semaphorin receptors results in a range of cellular responses, including axon repulsion, immune cell activation, fibroblast proliferation, and pericyte contraction. In the amygdala, SEMA6D tunes circuits for emotional, metabolic, and inflammatory outputs. These outcomes demonstrate the broad physiological impact of semaphorin receptor activity.
Key Genes Involved in GO:0017154 semaphorin receptor activity
The following genes encode receptors, co-receptors, and ligands that mediate semaphorin receptor activity (GO:0017154) and are frequently studied in cancer, fibrosis, and neurobiology.
| Gene | Major Role | Research Relevance |
|---|---|---|
| NRP2 | Co-receptor for SEMA3C; activates MAPK | Promotes colorectal cancer liver metastasis |
| PLXNB1 | Receptor for SEMA4D; activates pericytes | Drives neovascular AMD |
| PLXND1 | Receptor for SEMA3E; activates ErbB2 | Mediates lung fibrosis |
| PLXNA1 | Receptor for SEMA6D; tunes amygdalar circuits | Regulates emotional and metabolic outputs |
| SEMA3C | Ligand for NRP2; reshapes stroma | Promotes HCC progression and liver fibrosis |
| SEMA4D | Ligand for PlexinB1; activates pericytes | Aggravates neovascular AMD |
| SEMA3E | Ligand for PlexinD1; activates fibroblasts | Drives lung fibrosis |
| SEMA6D | Ligand for PlexinA1; regulates circuits | Modulates amygdala function |
| CD72 | Receptor for SEMA4D in immune cells | Regulates immune responses |
| NRP1 | Co-receptor for class 3 semaphorins | Modulates axon guidance and angiogenesis |
| PLXNA2 | Receptor for class 3 and 6 semaphorins | Involved in neural development |
| PLXNA3 | Receptor for SEMA6A | Regulates axon guidance |
| PLXNA4 | Receptor for SEMA6A | Implicated in Alzheimer's disease |
| PLXNB2 | Receptor for SEMA4C | Regulates cell migration |
| PLXNC1 | Receptor for SEMA7A | Modulates immune responses |
| SEMA4A | Ligand for PlexinB and D1 | Regulates T-cell activation |
| SEMA7A | Ligand for PlexinC1 | Promotes inflammation |
How Is semaphorin receptor activity Regulated?
Semaphorin receptor activity is regulated at multiple levels, including ligand availability, receptor expression, and post-translational modifications. For example, SEMA3C expression is upregulated in cancer-associated fibroblasts and reshapes the stromal microenvironment to promote hepatocellular carcinoma progression. In liver fibrosis, SEMA3C exacerbates fibrosis through receptor-mediated signaling. Additionally, SEMA4D-PlexinB1 signaling in pericytes is aggravated by smoking, linking environmental factors to receptor activity. These examples illustrate that semaphorin receptor activity is dynamically controlled by both intrinsic and extrinsic cues.
semaphorin receptor activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| NRP2 | Colorectal cancer liver metastasis | Knockout in cancer cells or organoids |
| SEMA3C | Liver fibrosis and HCC progression | Overexpression or knockout in hepatic stellate cells |
| PLXND1 | Lung fibrosis | Knockout in lung fibroblasts |
| PLXNB1 | Neovascular AMD | Knockout in pericytes |
| SEMA6D | Amygdalar circuit dysfunction | Knockout in mouse neurons |
Semaphorin receptor activity in cancer metastasis
Semaphorin receptors promote cancer progression and metastasis. Cancer-associated fibroblast-derived SEMA3C facilitates colorectal cancer liver metastasis via NRP2-mediated MAPK activation. SEMA3C also reshapes the stromal microenvironment to promote hepatocellular carcinoma progression. In pancreatic cancer, axon guidance molecules including semaphorins promote perineural invasion and metastasis. These findings establish semaphorin receptor activity as a driver of aggressive cancer phenotypes.
Semaphorin receptor activity in fibrosis
Semaphorin signaling contributes to fibrosis in multiple organs. SEMA3C exacerbates liver fibrosis by activating hepatic stellate cells. In lung fibrosis, the SEMA3E-PlexinD1 axis drives fibroblast activation through ErbB2. These studies highlight semaphorin receptors as potential therapeutic targets for fibrotic diseases.
Semaphorin receptor activity in neovascular age-related macular degeneration
Smoking aggravates neovascular age-related macular degeneration via the Sema4D-PlexinB1 axis, which activates pericytes. This demonstrates that semaphorin receptor activity in vascular cells contributes to AMD pathogenesis and may be modulated to treat the disease.
Semaphorin receptor activity in neuropsychiatric and metabolic disorders
Semaphorin 6D tunes amygdalar circuits for emotional, metabolic, and inflammatory outputs, indicating that semaphorin receptor activity in the brain influences systemic physiology. This expands the relevance of GO:0017154 beyond classical axon guidance.
From semaphorin receptor activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does NRP2 mediate SEMA3C-induced MAPK activation? | NRP2 knockout colorectal cancer cells |
| Does SEMA3C promote liver fibrosis? | SEMA3C overexpression in hepatic stellate cells |
| Does PlexinD1 drive lung fibrosis? | PlexinD1 knockout in lung fibroblasts |
| Does PlexinB1 activation in pericytes aggravate AMD? | PlexinB1 knockout pericytes |
| Does SEMA6D tune amygdalar circuits? | SEMA6D knockout mice |
| Does SEMA4D binding to CD72 regulate immune responses? | CD72 point-mutant immune cells |
How to Study the semaphorin receptor activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Gene essentiality for semaphorin signaling | Identify NRP2 as required for SEMA3C-induced MAPK |
| RNA-seq | Transcriptional changes | Profile gene expression after SEMA4D-PlexinB1 activation |
| Phosphoproteomics | Phosphorylation events | Detect ErbB2 activation by SEMA3E-PlexinD1 |
| Live-cell imaging | Cellular dynamics | Measure pericyte contraction in response to SEMA4D |
| Migration assay | Cell motility | Assess SEMA3C-induced cancer cell migration |
| Fibrosis assays | Collagen deposition | Evaluate SEMA3C-induced liver fibrosis |
| Electrophysiology | Neuronal activity | Study SEMA6D effects on amygdalar circuits |
| Flow cytometry | Immune cell activation | Analyze CD72 signaling in immune cells |
CRISPR knockout screens to identify semaphorin receptor dependencies
Genome-wide CRISPR knockout screens can systematically identify genes required for semaphorin receptor activity. For example, knocking out NRP2 in colorectal cancer cells can test its requirement for SEMA3C-induced MAPK activation and metastasis. Similar screens in hepatic stellate cells can reveal mediators of SEMA3C-driven liver fibrosis.
Transcriptomics and proteomics to map signaling networks
RNA-seq and phosphoproteomics can map the downstream signaling networks activated by semaphorin receptors. In lung fibrosis, SEMA3E-PlexinD1 signaling activates ErbB2, which can be detected by phosphoproteomics. In pericytes, SEMA4D-PlexinB1 activation alters gene expression programs that can be profiled by RNA-seq.
Imaging and functional assays to assess cellular responses
Live-cell imaging and functional assays such as migration, proliferation, and contraction assays can measure the outcomes of semaphorin receptor activity. For instance, pericyte contraction in response to SEMA4D can be imaged, and fibroblast activation in lung fibrosis can be quantified.
Animal models to study semaphorin receptor activity in vivo
Mouse models with conditional knockout or overexpression of semaphorin receptors are valuable for studying their roles in disease. For example, SEMA6D knockout mice reveal amygdalar circuit dysfunction, and SEMA3C overexpression in mice exacerbates liver fibrosis.
How CRISPR Can Be Used to Study GO:0017154 semaphorin receptor activity
Knockout
CRISPR knockout of semaphorin receptors such as NRP2, PLXNB1, or PLXND1 can abolish ligand-induced signaling and reveal their causal roles in cancer, fibrosis, and AMD. For example, NRP2 knockout in colorectal cancer cells blocks SEMA3C-induced MAPK activation and liver metastasis.
Point Mutation
Point mutations can dissect specific domains or residues required for semaphorin receptor activity. For instance, mutating the GTPase-activating protein domain of plexins can test its contribution to signal transduction. Such models are useful for understanding structure-function relationships.
Knock-in
Knock-in of tagged or fluorescently labeled semaphorin receptors allows real-time tracking of receptor localization and dynamics. For example, knocking in a GFP tag on PLXNB1 can visualize its trafficking in pericytes. This approach is valuable for studying receptor internalization and recycling.
Overexpression
Overexpression of semaphorin ligands or receptors can model gain-of-function phenotypes observed in disease. For example, SEMA3C overexpression in hepatic stellate cells exacerbates liver fibrosis, and SEMA4D overexpression in pericytes aggravates AMD-like pathology. These models help validate therapeutic targets.
How EDITGENE Supports semaphorin receptor activity Research
Researchers studying semaphorin receptor activity-related genes often need to determine whether a candidate gene is causally involved in signaling, disease progression, or therapeutic response. EDITGENE provides custom CRISPR cell models and screening services to accelerate this discovery process.
Contact EDITGENE today to design your custom CRISPR model for semaphorin receptor activity research.
Frequently Asked Questions About semaphorin receptor activity
What is semaphorin receptor activity?
Semaphorin receptor activity (GO:0017154) is a molecular function where a receptor binds a semaphorin ligand and transmits a signal across the membrane to change cell activity.
What genes are involved in semaphorin receptor activity?
Key genes include NRP2, PLXNB1, PLXND1, PLXNA1, CD72, and ligands such as SEMA3C, SEMA4D, SEMA3E, and SEMA6D.
How does semaphorin receptor activity contribute to cancer?
It promotes metastasis through pathways like SEMA3C-NRP2-MAPK in colorectal cancer and SEMA3C-driven HCC progression.
What diseases are linked to semaphorin receptor activity?
Diseases include cancer metastasis, liver fibrosis, lung fibrosis, neovascular AMD, and neuropsychiatric disorders.
How can I study semaphorin receptor activity using CRISPR?
CRISPR knockout, point mutation, knock-in, and overexpression models can dissect receptor function in disease.
What is the role of NRP2 in semaphorin receptor activity?
NRP2 acts as a co-receptor for SEMA3C and mediates MAPK activation to drive colorectal cancer liver metastasis.
What is the SEMA4D-PlexinB1 axis?
It is a signaling pathway where SEMA4D binds PlexinB1 to activate pericytes, contributing to neovascular AMD.
How does SEMA3E-PlexinD1 signaling work?
SEMA3E binds PlexinD1 to activate ErbB2 in fibroblasts, driving lung fibrosis.
What is the role of SEMA6D in the brain?
SEMA6D tunes amygdalar circuits for emotional, metabolic, and inflammatory outputs.
What services does EDITGENE offer for semaphorin receptor research?
EDITGENE provides knockout, point mutation, knock-in, overexpression cell models, CRISPR library screening, and bioinformatics services.
Conclusion
Semaphorin receptor activity (GO:0017154) is a fundamental molecular function that translates extracellular semaphorin cues into diverse cellular responses, with critical roles in development, immunity, cancer, and fibrosis. Understanding its mechanisms through CRISPR-based models and multi-omics approaches can reveal new therapeutic targets for major human diseases. EDITGENE offers comprehensive services to support these research efforts.
References
- 1. Zhang Y et al.. 2025. Cancer-associated fibroblast-derived SEMA3C facilitates colorectal cancer liver metastasis via NRP2-mediated MAPK activation.. Proc Natl Acad Sci U S A 122(21):e2423077122 PMID: 40402249
- 2. Kuklina EM. 2019. Receptor Functions of Semaphorin 4D.. Biochemistry (Mosc) 84(9):1021-1027 PMID: 31693461
- 3. Peng H et al.. 2024. Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression.. Signal Transduct Target Ther 9(1):169 PMID: 38956074
- 4. De Angelis Rigotti F et al.. 2023. Semaphorin 3C exacerbates liver fibrosis.. Hepatology 78(4):1092-1105 PMID: 37055018
- 5. Jurcak NR et al.. 2019. Axon Guidance Molecules Promote Perineural Invasion and Metastasis of Orthotopic Pancreatic Tumors in Mice.. Gastroenterology 157(3):838-850.e6 PMID: 31163177
- 6. Deng Z et al.. 2025. Semaphorin 3E-Plexin D1 Axis Drives Lung Fibrosis through ErbB2-Mediated Fibroblast Activation.. Adv Sci (Weinh) 12(18):e2415007 PMID: 40112179
- 7. He K et al.. 2025. Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes.. Nat Commun 16(1):2821 PMID: 40121188
- 8. Nakanishi Y et al.. 2024. Semaphorin 6D tunes amygdalar circuits for emotional, metabolic, and inflammatory outputs.. Neuron 112(17):2955-2972.e9 PMID: 39002542
