GO:0035728 response to hepatocyte growth factor: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035728 (response to hepatocyte growth factor) describes any cellular or organismal change triggered by hepatocyte growth factor (HGF), including movement, secretion, enzyme production, and gene expression.
• HGF signals primarily through the MET receptor tyrosine kinase, and this axis is a central driver of cell survival, proliferation, migration, and morphogenesis in development and tissue repair.
• Dysregulated HGF/MET signaling is implicated in multiple cancers, including lung, colorectal, and brain tumors, where it promotes tumorigenesis and therapy resistance.
• HGF also contributes to non-cancer processes such as fracture repair by upregulating BMP receptors, and its levels can predict outcomes in hepatitis C.
• Studying GO:0035728 requires integrated approaches including CRISPR knockout, point mutation, knock-in, overexpression, and CRISPR library screening to dissect causal gene contributions.
• EDITGENE provides end-to-end CRISPR cell model and bioinformatics services to accelerate functional validation of HGF-responsive genes.
Description
GO:0035728, response to hepatocyte growth factor, is a biological process term in the Gene Ontology that captures any change in a cell or organism's state or activity as a result of a hepatocyte growth factor (HGF) stimulus. This includes alterations in movement, secretion, enzyme production, and gene expression, making it a broad and integrative process that touches on development, tissue repair, and disease. HGF is a pleiotropic cytokine that primarily signals through the MET receptor tyrosine kinase, and its downstream effects are critical for coordinating complex cellular behaviors. Researchers study this term to understand how a single growth factor can orchestrate diverse outcomes such as cell scattering, proliferation, and survival, and how these responses go awry in conditions like cancer and chronic infection. The importance of GO:0035728 extends beyond basic biology; it is a focal point for therapeutic development because HGF/MET signaling is frequently dysregulated in human malignancies and is a target for kinase inhibitors. In lung cancer, for example, fibroblast subtypes that produce HGF can shape distinct therapeutic paradigms, highlighting the clinical relevance of this response process. Similarly, in colorectal cancer, HGF/MET and CD44 cooperate to drive tumorigenesis and resistance to therapy, underscoring the need to understand the molecular underpinnings of this GO term.
response to hepatocyte growth factor At A Glance
| GO ID | GO:0035728 |
|---|---|
| GO term | response to hepatocyte growth factor |
| Ontology | biological_process |
| Synonym | response to hepatocyte growth factor stimulus; response to HGF stimulus |
| Major function | Mediates cellular and organismal changes triggered by HGF, including movement, secretion, enzyme production, and gene expression |
| Primary receptor | MET (hepatocyte growth factor receptor) |
| Key downstream pathways | PI3K-AKT, MAPK/ERK, and other signaling cascades |
| Physiological roles | Tissue repair, development, and regeneration |
| Pathological roles | Cancer progression, therapy resistance, and chronic infection outcomes |
What Is GO:0035728?
In simple terms, GO:0035728 describes everything that happens inside a cell or organism after it encounters hepatocyte growth factor (HGF). According to the Gene Ontology, it is any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an HGF stimulus. This definition encompasses the immediate signaling events triggered by HGF binding to its receptor MET, as well as the downstream transcriptional, metabolic, and behavioral changes that follow. The term is intentionally broad to include diverse outcomes such as cell migration, proliferation, survival, and differentiation, all of which are influenced by HGF in various physiological and pathological contexts.
Why Is response to hepatocyte growth factor Important in Cell Biology?
Understanding GO:0035728 is critical because HGF is a master regulator of cell behavior, and its responses are implicated in a wide range of physiological and pathological processes. From embryonic development to wound healing and cancer, the HGF/MET axis controls cell survival, proliferation, and migration. In cancer, HGF produced by the tumor microenvironment can activate MET on cancer cells, driving tumorigenesis and resistance to targeted therapies. In infectious diseases, HGF levels correlate with disease severity and response to therapy, as seen in hepatitis C. Moreover, HGF contributes to bone fracture repair by upregulating BMP receptors, demonstrating its role beyond oncology. Studying this process helps identify therapeutic targets and biomarkers, and it informs the development of MET inhibitors and other interventions.
• HGF/MET signaling is a major driver of cancer cell proliferation, survival, and metastasis in multiple tumor types.
• The response to HGF is essential for normal tissue repair, including bone fracture healing via BMP receptor upregulation.
• HGF levels can predict outcome and response to therapy in hepatitis C, linking this process to infectious disease management.
• In colorectal cancer, HGF/MET cooperates with CD44 to promote tumorigenesis and therapy resistance.
• HGF sensitizes brain tumors to c-MET kinase inhibition, revealing context-dependent therapeutic opportunities.
• Oxidative stress can modulate HGF-dependent pro-senescence activity in ovarian cancer cells.
• Lung cancer fibroblasts that produce HGF define distinct therapeutic paradigms, highlighting the importance of the tumor microenvironment.
• HGF stimulates chemokine receptors in oral fibroblasts, identifying potential wound healing targets.
• Understanding GO:0035728 aids in the development of biomarkers and targeted therapies for HGF-driven diseases.
• CRISPR-based models are essential to dissect the causal roles of genes involved in the HGF response.
What Happens During response to hepatocyte growth factor?
HGF Binding and MET Activation
In simple terms: HGF acts like a key that fits into the MET lock on the cell surface, turning on a series of signals inside the cell.
The response to hepatocyte growth factor begins when HGF binds to its high-affinity receptor, MET, a receptor tyrosine kinase. This binding induces MET dimerization and autophosphorylation, creating docking sites for adaptor proteins that propagate downstream signaling. In cancer, this step is often hijacked; for instance, in colorectal cancer, HGF/MET signaling is a key driver of tumorigenesis and therapy resistance. The activation of MET triggers a cascade of intracellular events that ultimately lead to changes in gene expression, cell movement, and survival.
Downstream Signaling Cascades
In simple terms: Once MET is activated, it sends signals through multiple intracellular pathways that tell the cell to grow, move, or survive.
Activated MET recruits and activates several downstream pathways, most notably the PI3K-AKT and MAPK/ERK cascades. These pathways regulate diverse cellular processes such as proliferation, migration, and apoptosis. In brain tumors, HGF sensitizes cells to c-MET kinase inhibition, indicating that the downstream signaling is critical for therapeutic response. Similarly, in ovarian cancer cells, oxidative stress contributes to HGF-dependent pro-senescence activity, showing that the cellular context modulates these cascades. The integration of these signals determines the overall response to HGF.
Cellular and Organismal Responses
In simple terms: The signals lead to actual changes in how the cell behaves, such as moving, dividing, or producing new proteins.
The ultimate outcomes of the response to HGF include changes in cell movement, secretion, enzyme production, and gene expression. For example, HGF stimulates oral fibroblast chemokine receptors, identifying CCR3 and CCR4 as potential wound healing targets. In bone, HGF contributes to fracture repair by upregulating the expression of BMP receptors, demonstrating a role in tissue regeneration. These responses are essential for normal physiology but can become dysregulated in disease, such as in hepatitis C where HGF levels predict outcome and response to therapy.
Modulation by the Microenvironment
In simple terms: Other cells and factors around the cell can influence how it responds to HGF.
The response to HGF is not cell-autonomous; it is heavily influenced by the tumor microenvironment and other stimuli. In lung cancer, three subtypes of fibroblasts define distinct therapeutic paradigms, with some fibroblasts producing HGF that affects cancer cells. In colorectal cancer, CD44 partners with HGF/MET to promote tumorigenesis and therapy resistance, illustrating how co-receptors and matrix components modulate the response. Oxidative stress can also shift the response towards pro-senescence in ovarian cancer cells. Thus, the context determines whether HGF promotes growth, survival, or senescence.
Key Genes Involved in GO:0035728 response to hepatocyte growth factor
The following genes and proteins are central to the response to hepatocyte growth factor (GO:0035728), based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| HGF | Ligand that binds MET to initiate signaling | Central to the response; levels predict outcomes in hepatitis C |
| MET | Receptor tyrosine kinase for HGF | Key driver of cancer and target of inhibitors |
| CD44 | Co-receptor that partners with MET | Promotes tumorigenesis and therapy resistance in colorectal cancer |
| PIK3CA | Catalytic subunit of PI3K, downstream of MET | Mediates survival signaling; often mutated in cancer |
| AKT1 | Serine/threonine kinase in PI3K pathway | Promotes cell survival and proliferation |
| MAPK1 | ERK2, downstream of RAS | Regulates proliferation and migration |
| MAPK3 | ERK1, downstream of RAS | Regulates proliferation and migration |
| BMPR1A | BMP receptor upregulated by HGF | Mediates fracture repair |
| BMPR1B | BMP receptor upregulated by HGF | Mediates fracture repair |
| CCR3 | Chemokine receptor stimulated by HGF | Potential wound healing target |
| CCR4 | Chemokine receptor stimulated by HGF | Potential wound healing target |
| GAB1 | Adaptor protein docking to MET | Propagates downstream signaling |
| GRB2 | Adaptor protein linking MET to RAS | Activates MAPK pathway |
| SRC | Non-receptor tyrosine kinase | Modulates MET signaling |
| STAT3 | Transcription factor downstream of MET | Regulates gene expression |
| VEGFA | Angiogenic factor induced by HGF | Promotes angiogenesis in tumors |
| MMP9 | Matrix metalloproteinase induced by HGF | Facilitates invasion and metastasis |
How Is response to hepatocyte growth factor Regulated?
The response to hepatocyte growth factor (GO:0035728) is tightly regulated at multiple levels. Receptor availability and activity are controlled by MET internalization, degradation, and feedback phosphorylation. Downstream, the PI3K-AKT and MAPK pathways are modulated by phosphatases and other negative regulators. In cancer, oxidative stress can shift the response towards senescence in ovarian cancer cells. Additionally, the tumor microenvironment, including fibroblasts, can provide paracrine HGF that sustains signaling. CD44 can also modulate MET activation and downstream effects in colorectal cancer. These regulatory mechanisms ensure that the response is context-dependent and reversible, but they are often disrupted in disease.
response to hepatocyte growth factor and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MET | Colorectal cancer, therapy resistance | Knockout or point mutation in HCT116 cells |
| HGF | Hepatitis C outcome | Overexpression in hepatoma cell lines |
| CD44 | Colorectal cancer tumorigenesis | Knockout in colorectal cancer organoids |
| BMPR1A | Fracture repair | Knock-in of BMPR1A in osteoblasts |
| CCR3 | Wound healing | Overexpression in oral fibroblasts |
Cancer
Dysregulated response to HGF is a hallmark of many cancers. In lung cancer, fibroblast subtypes that produce HGF define distinct therapeutic paradigms, influencing tumor progression and drug response. In colorectal cancer, HGF/MET and CD44 cooperate to drive tumorigenesis and resistance to therapy. Brain tumors can be sensitized to c-MET kinase inhibition by HGF, suggesting that the response pathway is a therapeutic target. Ovarian cancer cells can undergo HGF-dependent pro-senescence under oxidative stress, revealing complex roles in tumor suppression and progression.
Infectious Diseases
HGF levels are a predictor of outcome and response to therapy in hepatitis C, linking the response to HGF with infectious disease progression. HGF also plays a role in physiology and infectious diseases more broadly, as reviewed in the literature.
Tissue Repair and Regeneration
HGF contributes to fracture repair by upregulating the expression of BMP receptors, demonstrating its importance in bone healing. In oral fibroblasts, HGF stimulates chemokine receptors CCR3 and CCR4, identifying potential targets for wound healing.
From response to hepatocyte growth factor-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does MET kinase activity drive HGF-induced migration? | Point mutation (kinase-dead MET) in cancer cell lines |
| What is the role of CD44 in HGF/MET-mediated therapy resistance? | Knockout of CD44 in colorectal cancer cells |
| Can HGF-induced BMP receptor upregulation be enhanced? | Knock-in of BMPR1A/B in osteoblasts |
| Which genes are essential for HGF response in lung fibroblasts? | CRISPR library screening in primary fibroblasts |
| Does oxidative stress alter HGF-induced senescence? | Overexpression of antioxidant enzymes in ovarian cancer cells |
| How does HGF affect chemokine receptor expression? | Overexpression of CCR3/CCR4 in oral fibroblasts |
How to Study the response to hepatocyte growth factor Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify HGF-induced transcriptional programs |
| Phosphoproteomics | Phosphorylation of signaling proteins | Map MET downstream pathways |
| Live-cell imaging | Cell migration and morphological changes | Study HGF-induced scattering |
| CRISPR knockout screening | Gene essentiality and resistance | Find modifiers of HGF response |
| CRISPR knock-in | Tagged protein expression | Track MET localization |
| Western blot | Protein expression and phosphorylation | Validate specific pathway activation |
| ELISA | Secreted HGF levels | Correlate with disease outcome |
| Flow cytometry | Cell surface receptor expression | Measure CCR3/CCR4 after HGF stimulation |
Transcriptomic Profiling
RNA sequencing (RNA-seq) is widely used to measure changes in gene expression following HGF stimulation, revealing the transcriptional programs activated during the response. This method can identify novel HGF-responsive genes and pathways, and it is often combined with CRISPR perturbations to establish causality.
Proteomic and Phosphoproteomic Analysis
Mass spectrometry-based proteomics can quantify protein abundance and phosphorylation changes downstream of MET activation, providing a global view of signaling events. This is particularly useful for identifying feedback loops and off-target effects of MET inhibitors.
Imaging and Live-Cell Assays
Fluorescence microscopy and live-cell imaging allow researchers to visualize HGF-induced cell scattering, migration, and morphological changes in real time. These techniques are essential for understanding the dynamic nature of the response.
CRISPR-Based Functional Genomics
CRISPR knockout, knock-in, and library screening enable systematic dissection of gene function in the HGF response. For example, genome-wide screens can identify genes that modulate sensitivity to MET inhibition.
How CRISPR Can Be Used to Study GO:0035728 response to hepatocyte growth factor
Knockout
CRISPR knockout is used to delete genes such as MET or CD44 to determine their necessity in the response to HGF. For example, knocking out MET in cancer cell lines abolishes HGF-induced migration and survival, confirming its central role. Knockout of CD44 in colorectal cancer cells reduces tumorigenesis and therapy resistance.
Point Mutation
Point mutations can be introduced to study specific residues in MET or downstream effectors. For instance, kinase-dead MET mutants can distinguish between kinase-dependent and independent functions. Such models are valuable for testing targeted inhibitors.
Knock-in
Knock-in of tagged proteins (e.g., GFP-MET) allows real-time tracking of receptor localization and dynamics. Knock-in of BMP receptors can enhance fracture repair in models. This approach is also used to create reporter cell lines for high-throughput screening.
Overexpression
Overexpression of HGF or MET can mimic pathological states such as cancer. For example, overexpressing HGF in hepatoma cells can model hepatitis C outcomes. Overexpression of CCR3/CCR4 in oral fibroblasts can enhance wound healing responses.
How EDITGENE Supports response to hepatocyte growth factor Research
Researchers studying response to hepatocyte growth factor-related genes often need to determine whether a candidate gene is causally involved in the process or merely correlated with it. This requires precise genetic manipulation, which is where EDITGENE's CRISPR services can accelerate discovery.
Contact EDITGENE today to design your custom CRISPR model for response to hepatocyte growth factor research.
Frequently Asked Questions About response to hepatocyte growth factor
What is GO:0035728?
GO:0035728 is the Gene Ontology term for 'response to hepatocyte growth factor', defined as any process that results in a change in state or activity of a cell or an organism as a result of an HGF stimulus.
What genes are involved in response to hepatocyte growth factor?
Key genes include HGF, MET, CD44, and downstream effectors such as PI3K, AKT, and MAPK.
How does HGF signaling work?
HGF binds to the MET receptor, triggering autophosphorylation and activation of downstream pathways like PI3K-AKT and MAPK/ERK, leading to changes in gene expression and cell behavior.
What diseases are associated with HGF response?
Cancers such as lung, colorectal, and brain tumors, as well as hepatitis C and impaired fracture healing, are linked to HGF response.
How can I study response to hepatocyte growth factor in the lab?
Common methods include RNA-seq, phosphoproteomics, live-cell imaging, and CRISPR-based perturbations.
What is the role of MET in HGF response?
MET is the primary receptor for HGF and mediates most of the downstream signaling that defines the response.
Can CRISPR be used to study HGF response?
Yes, CRISPR knockout, knock-in, and library screening are powerful tools to dissect gene function in the HGF response.
What are the therapeutic implications of HGF/MET signaling?
Inhibiting MET or HGF can block tumor growth and overcome therapy resistance, making this pathway a drug target.
How does oxidative stress affect HGF response?
Oxidative stress can shift HGF response towards pro-senescence in ovarian cancer cells.
What services does EDITGENE offer for HGF research?
EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression, library screening, and bioinformatics services tailored to HGF-related genes.
Conclusion
The response to hepatocyte growth factor (GO:0035728) is a fundamental biological process that integrates extracellular cues into diverse cellular outcomes, from proliferation and migration to tissue repair and disease progression. Its dysregulation is central to cancer, infectious diseases, and impaired regeneration, making it a high-priority area for research and therapeutic development. By leveraging CRISPR-based models and advanced bioinformatics, researchers can uncover the precise genetic players and mechanisms, ultimately translating these insights into clinical advances.
References
- 1. Hu H et al.. 2021. Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms.. Cancer Cell 39(11):1531-1547.e10 PMID: 34624218
- 2. Imamura R et al.. 2017. Hepatocyte growth factor in physiology and infectious diseases.. Cytokine 98:97-106 PMID: 28094206
- 3. Zhang Y et al.. 2013. Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition.. Clin Cancer Res 19(6):1433-44 PMID: 23386689
- 4. Mikuła-Pietrasik J et al.. 2017. Oxidative stress contributes to hepatocyte growth factor-dependent pro-senescence activity of ovarian cancer cells.. Free Radic Biol Med 110:270-279 PMID: 28652056
- 5. Joosten SPJ et al.. 2020. Hepatocyte growth factor/MET and CD44 in colorectal cancer: partners in tumorigenesis and therapy resistance.. Biochim Biophys Acta Rev Cancer 1874(2):188437 PMID: 32976979
- 6. Imai Y et al.. 2005. Hepatocyte growth factor contributes to fracture repair by upregulating the expression of BMP receptors.. J Bone Miner Res 20(10):1723-30 PMID: 16160730
- 7. García-Pajares F et al.. 2010. Hepatocyte growth factor (HGF): a predictor of outcome and response to therapy in hepatitis C?. Rev Esp Enferm Dig 102(6):349-51 PMID: 20575593
- 8. Buskermolen JK et al.. 2017. Stimulation of oral fibroblast chemokine receptors identifies CCR3 and CCR4 as potential wound healing targets.. J Cell Physiol 232(11):2996-3005 PMID: 28387445
