GO:2001113 negative regulation of cellular response to hepatocyte growth factor stimulus: Signaling Brake, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:2001113 describes any process that stops, prevents, or reduces the cellular response to hepatocyte growth factor (HGF) stimulation.
• HGF signaling is normally pro-migratory and pro-survival; its negative regulation is essential to prevent excessive cell motility and uncontrolled proliferation.
• Key negative regulators include phosphatases (e.g., PTEN, PTPN11), endocytic adaptors (e.g., CBL), and Rho/ROCK pathway components that dampen HGF-induced chemotaxis.
• Dysregulation of this term is linked to cancer progression, chronic wound healing defects, and fibrotic diseases.
• Experimental models for studying this process include CRISPR knockout of negative regulators, phospho-proteomics, and live-cell imaging of HGF-dependent migration.
• EDITGENE provides CRISPR cell models (KO, point mutation, knock-in, overexpression) and library screening to dissect this regulatory axis.
Description
The Gene Ontology term GO:2001113, negative regulation of cellular response to hepatocyte growth factor stimulus, defines any biological process that stops, prevents, or reduces the frequency, rate, or extent of a cell's response to hepatocyte growth factor (HGF). HGF is a pleiotropic cytokine that activates the MET receptor tyrosine kinase, driving cell scattering, proliferation, survival, and migration. Because unrestrained HGF signaling can promote tumor invasion and metastasis, cells have evolved multiple layers of negative regulation to keep this pathway in check. Understanding these brakes is critical for cancer biology, tissue regeneration, and wound healing research. This article synthesizes authoritative QuickGO annotations and real PubMed literature to provide a research-grade overview of GO:2001113, its molecular players, and experimental strategies for its study.
negative regulation of cellular response to hepatocyte growth factor stimulus At A Glance
| GO ID | GO:2001113 |
|---|---|
| GO term | negative regulation of cellular response to hepatocyte growth factor stimulus |
| Ontology | biological_process |
| Synonym | negative regulation of cellular response to HGF stimulus |
| Major function | Dampening HGF-induced cellular responses such as migration, proliferation, and survival |
| Related cellular component | Plasma membrane, endosomes, cytoskeleton |
| Related molecular function | Protein phosphatase activity, GTPase regulator activity, ubiquitin ligase activity |
| Regulated process | HGF/MET signaling, PI3K/AKT pathway, Rho/ROCK-mediated chemotaxis |
What Is GO:2001113?
GO:2001113 is a biological process term that encompasses any mechanism that negatively regulates the cellular response to HGF stimulation. This includes processes that reduce the frequency, rate, or extent of downstream signaling events such as MET phosphorylation, PI3K/AKT activation, or cell migration in response to HGF. The term is not restricted to a single molecular mechanism; it can involve receptor internalization, phosphatase-mediated dephosphorylation, or inhibition of downstream effectors.
Why Is negative regulation of cellular response to hepatocyte growth factor stimulus Important in Cell Biology?
Negative regulation of HGF signaling is essential for normal tissue homeostasis and for preventing pathological outcomes such as cancer metastasis and chronic non-healing wounds. HGF is a potent motogen and mitogen; without negative feedback, cells can become hyper-responsive to HGF, leading to excessive migration and invasion. This GO term therefore represents a critical node for therapeutic intervention in oncology and regenerative medicine.
• Prevents uncontrolled cell migration and invasion in response to HGF.
• Limits HGF-driven proliferation in epithelial and endothelial cells.
• Modulates wound healing by balancing HGF-induced repair and resolution.
• Dysregulation is associated with tumor progression and metastasis.
• Influences angiogenesis through HGF-induced endothelial chemotaxis.
• Provides targets for anti-metastatic therapies.
• Affects tissue regeneration by controlling HGF bioavailability.
• Involved in fibrotic diseases where HGF signaling is aberrant.
• Key for understanding resistance to MET-targeted therapies.
• Enables precise control of HGF-dependent developmental processes.
What Happens During negative regulation of cellular response to hepatocyte growth factor stimulus?
Receptor-level attenuation of HGF signaling
In simple terms: The cell reduces the number or activity of HGF receptors on its surface.
Negative regulation can occur at the receptor level through increased internalization and degradation of the MET receptor, or through dephosphorylation of activated MET by protein tyrosine phosphatases. This reduces the cell's ability to respond to HGF stimulation.
Inhibition of downstream PI3K/AKT and Rho/ROCK pathways
In simple terms: The cell blocks the internal signals that HGF uses to promote movement and survival.
HGF-induced chemotaxis involves G(ialpha2)-linked Rho kinase activity, and negative regulation can occur by inhibiting this pathway. For example, differential regulation of sphingosine-1-phosphate- and VEGF-induced endothelial cell chemotaxis involves Rho kinase, suggesting that similar mechanisms may dampen HGF responses.
Modulation of PAK4 and cytoskeletal dynamics
In simple terms: The cell alters proteins that control the cytoskeleton to stop HGF-driven shape changes.
PAK4 is activated via PI3K in HGF-stimulated epithelial cells, and negative regulation of this activation can prevent HGF-induced cell scattering and migration. This represents a key node where negative regulation intersects with cytoskeletal reorganization.
Temporal and differential proteomic control
In simple terms: The cell changes the abundance of many proteins over time to shut down HGF responses.
Proteomic profiling of chronic and acute wound healing has identified molecular mediators that are differentially expressed, some of which may negatively regulate HGF signaling to resolve repair. This suggests that negative regulation is a dynamic, multi-protein process.
Key Genes Involved in GO:2001113 negative regulation of cellular response to hepatocyte growth factor stimulus
The following genes and proteins have been implicated in the negative regulation of cellular response to HGF stimulus, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| MET | HGF receptor; negative regulation includes its downregulation | Target for knockout to study loss of negative feedback |
| PTEN | Lipid phosphatase that opposes PI3K/AKT | Knockout increases HGF sensitivity |
| PTPN11 | Protein tyrosine phosphatase SHP2; can attenuate MET signaling | Point mutations affect HGF response |
| CBL | E3 ubiquitin ligase; promotes MET degradation | Knockout stabilizes MET |
| RHOA | Small GTPase; mediates HGF-induced migration | Negative regulators of RhoA dampen HGF response |
| ROCK1 | Rho kinase; downstream of RhoA in HGF chemotaxis | Inhibition reduces HGF-induced migration |
| PAK4 | Serine/threonine kinase activated by HGF via PI3K | Knockout impairs HGF-induced cytoskeletal changes |
| PIK3CA | PI3K catalytic subunit; HGF activates PI3K | Negative regulation reduces PI3K activity |
| AKT1 | Survival kinase downstream of PI3K | Dephosphorylation attenuates HGF survival signals |
| GNAI2 | G(ialpha2) linked to Rho kinase in chemotaxis | Knockdown alters HGF-induced chemotaxis |
| S1PR1 | Sphingosine-1-phosphate receptor; cross-talks with HGF | Modulates endothelial chemotaxis |
| VEGFA | Angiogenic factor; shares pathways with HGF | Negative regulators may affect both |
| EGFR | Receptor tyrosine kinase; cross-talk with MET | Negative regulation may involve heterodimerization |
| CDH1 | E-cadherin; loss enhances HGF scattering | Negative regulation maintains cell junctions |
| MMP2 | Matrix metalloproteinase; HGF induces invasion | Negative regulators reduce MMP2 expression |
| TGFB1 | Cytokine that can antagonize HGF | Negative regulation may involve TGF-beta signaling |
| IL6 | Inflammatory cytokine; modulates HGF response | Chronic wound healing studies |
How Is negative regulation of cellular response to hepatocyte growth factor stimulus Regulated?
The negative regulation of HGF signaling is itself tightly controlled. For example, PI3K activation by HGF can be counteracted by PTEN, and Rho kinase activity can be modulated by G(ialpha2)-linked pathways. Additionally, PAK4 activation via PI3K is a point of negative regulation. Proteomic studies of wound healing suggest that temporal changes in protein expression, including phosphatases and ubiquitin ligases, orchestrate the shutdown of HGF responses.
negative regulation of cellular response to hepatocyte growth factor stimulus and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MET | Cancer, metastasis | Knockout of negative regulators in cancer cell lines |
| PTEN | Cancer, overgrowth syndromes | Point mutation knock-in to disrupt phosphatase activity |
| PTPN11 | Noonan syndrome, leukemia | Knock-in of disease-associated mutations |
| CBL | Leukemia, developmental disorders | Knockout to stabilize MET |
| PAK4 | Cancer, cell migration defects | Overexpression or knockout in epithelial cells |
Cancer progression and metastasis
Loss of negative regulation of HGF signaling can lead to sustained MET activation, promoting tumor cell invasion and metastasis. For example, decreased expression of phosphatases or ubiquitin ligases that normally degrade MET can enhance HGF-driven malignancy.
Chronic wound healing defects
Impaired negative regulation may contribute to chronic non-healing wounds, where excessive or prolonged HGF signaling disrupts normal repair. Proteomic profiling has identified molecular mediators associated with chronic versus acute wound healing.
Fibrotic diseases
Dysregulated HGF signaling is implicated in fibrosis; negative regulators that normally dampen HGF responses may be downregulated, leading to excessive fibroblast activation.
From negative regulation of cellular response to hepatocyte growth factor stimulus-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate HGF-induced migration? | CRISPR knockout of gene X in HGF-responsive cells |
| Does a point mutation in gene Y affect its ability to dampen HGF signaling? | Point mutation knock-in via CRISPR |
| Does tagging gene Z with a fluorescent protein alter its function? | Tagged knock-in |
| Does overexpression of gene W reduce HGF response? | Overexpression cell model |
| Which genes are essential for negative regulation? | CRISPR library screening |
| What is the phospho-proteomic signature upon negative regulator loss? | Quantitative proteomics |
How to Study the negative regulation of cellular response to hepatocyte growth factor stimulus Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Phospho-proteomics | Changes in protein phosphorylation | Identify negative feedback nodes |
| Live-cell imaging | Cell migration speed and direction | Assess HGF-induced chemotaxis |
| CRISPR knockout screening | Gene essentiality for negative regulation | Discover novel regulators |
| Western blot | Protein expression and phosphorylation | Validate specific candidates |
| Rho/ROCK activity assay | GTPase and kinase activity | Measure pathway inhibition |
| PAK4 kinase assay | PAK4 activation | Assess HGF-induced PAK4 activity |
| qPCR | mRNA levels of target genes | Confirm knockout or overexpression |
| Immunofluorescence | Subcellular localization | Visualize MET internalization |
Phospho-proteomics and temporal profiling
Quantitative proteomics can identify changes in phosphorylation of MET and downstream effectors upon HGF stimulation, revealing negative feedback loops. Temporal profiling of wound healing models has identified molecular mediators that may negatively regulate HGF.
Live-cell imaging of HGF-induced migration
Time-lapse microscopy can measure the rate and extent of cell migration in response to HGF, and how negative regulators alter these parameters.
CRISPR-based genetic screens
Genome-wide knockout screens can identify genes whose loss enhances HGF sensitivity, pinpointing negative regulators.
Biochemical assays for Rho/ROCK and PAK4 activity
Kinase activity assays and phospho-specific antibodies can measure the activation state of Rho/ROCK and PAK4, which are key nodes in HGF signaling.
How CRISPR Can Be Used to Study GO:2001113 negative regulation of cellular response to hepatocyte growth factor stimulus
Knockout
CRISPR knockout of candidate negative regulators (e.g., PTEN, CBL) can be used to test whether their loss enhances HGF-induced migration or proliferation. This approach is ideal for validating loss-of-function phenotypes.
Point Mutation
Point mutation knock-in can model disease-associated variants in genes like PTPN11 or MET, allowing precise assessment of their impact on negative regulation of HGF signaling.
Knock-in
Tagged knock-in (e.g., GFP or HA) of negative regulators enables live-cell imaging and biochemical tracking of their dynamics upon HGF stimulation.
Overexpression
Overexpression of putative negative regulators can suppress HGF-induced phenotypes, providing gain-of-function evidence for their role in GO:2001113.
How EDITGENE Supports negative regulation of cellular response to hepatocyte growth factor stimulus Research
Researchers studying negative regulation of cellular response to hepatocyte growth factor stimulus-related genes often need to determine whether a candidate gene is causally involved in dampening HGF signaling. EDITGENE provides a comprehensive suite of CRISPR services to enable such investigations.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of cellular response to hepatocyte growth factor stimulus research.
Frequently Asked Questions About negative regulation of cellular response to hepatocyte growth factor stimulus
What is GO:2001113?
GO:2001113 is a Gene Ontology term for any process that negatively regulates the cellular response to hepatocyte growth factor stimulus.
What genes are involved in negative regulation of HGF signaling?
Genes such as PTEN, CBL, PTPN11, PAK4, and RHOA have been implicated in dampening HGF responses.
How does HGF signaling get turned off?
It can be turned off by receptor internalization, phosphatase activity, or inhibition of downstream effectors like PI3K/AKT and Rho/ROCK.
Why is negative regulation of HGF important in cancer?
Loss of negative regulation can lead to sustained MET activation, promoting tumor invasion and metastasis.
What experimental models study GO:2001113?
CRISPR knockout, point mutation knock-in, overexpression, phospho-proteomics, and live-cell imaging are commonly used.
Which proteins are key nodes in HGF negative regulation?
MET, PTEN, CBL, PAK4, and Rho/ROCK are critical nodes.
How does PAK4 relate to HGF signaling?
PAK4 is activated via PI3K in HGF-stimulated epithelial cells and is a point of negative regulation.
What is the role of Rho kinase in HGF response?
Rho kinase mediates HGF-induced chemotaxis, and its inhibition can negatively regulate this response.
Can CRISPR screens identify new negative regulators?
Yes, genome-wide knockout screens can uncover genes whose loss enhances HGF sensitivity.
What diseases are linked to dysregulated HGF negative regulation?
Cancer, chronic wounds, and fibrotic diseases have been associated with altered negative regulation.
Conclusion
GO:2001113, negative regulation of cellular response to hepatocyte growth factor stimulus, is a critical biological process that prevents excessive HGF-driven cell migration, proliferation, and survival. Its dysregulation contributes to cancer, chronic wounds, and fibrosis. Understanding the molecular players and mechanisms requires robust experimental models, and CRISPR-based approaches offer powerful tools for dissecting this regulatory axis. EDITGENE provides comprehensive services to accelerate such research.
References
- 1. Zaidi MB et al.. 2024. Temporal and differential proteomic profile of molecular mediators associated with chronic and acute wound healing.. Cell Biochem Funct 42(2):e3946 PMID: 38379227
- 2. Liu F et al.. 2001. Differential regulation of sphingosine-1-phosphate- and VEGF-induced endothelial cell chemotaxis. Involvement of G(ialpha2)-linked Rho kinase activity.. Am J Respir Cell Mol Biol 24(6):711-9 PMID: 11415936
- 3. Wells CM et al.. 2002. PAK4 is activated via PI3K in HGF-stimulated epithelial cells.. J Cell Sci 115(Pt 20):3947-56 PMID: 12244132
