GO:1902204 positive regulation of hepatocyte growth factor receptor signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902204 describes any process that activates or increases the frequency, rate or extent of hepatocyte growth factor (HGF) receptor signaling, where the receptor is the MET tyrosine kinase.
• Positive regulation of MET signaling is essential for normal development, tissue repair, and cell motility, but its dysregulation drives cancer progression and fibrosis.
• Key positive regulators include the ligand HGF, the adaptor GRB2, and downstream effectors such as AKT and Rac1.
• Experimental models for studying this process include hepatocyte-specific knockout mice, point-mutant MET knock-in cells, and overexpression systems.
• CRISPR-based knockout, knock-in, and overexpression platforms enable precise interrogation of positive regulators in MET signaling.
• Understanding GO:1902204 has therapeutic implications for cancers with MET activation, including EGFR-mutant non-small cell lung cancer and liver fibrosis.
Description
The Gene Ontology (GO) term GO:1902204, positive regulation of hepatocyte growth factor receptor signaling pathway, defines any biological process that activates or increases the frequency, rate or extent of signaling downstream of the hepatocyte growth factor (HGF) receptor, also known as MET. This term is a child of the broader regulation of HGF receptor signaling and is critical for understanding how cells amplify MET-driven responses. MET is a receptor tyrosine kinase that, upon HGF binding, undergoes autophosphorylation and recruits adaptor proteins such as GRB2 to initiate downstream cascades including the PI3K-AKT and MAPK pathways. Positive regulation of this pathway is essential for embryogenesis, wound healing, and tissue regeneration, but aberrant activation contributes to tumorigenesis, metastasis, and fibrosis. Researchers study GO:1902204 to identify molecular mechanisms that enhance MET signaling, such as ligand availability, receptor dimerization, and effector protein interactions. For example, GRB2 is a positive regulator of MET signaling in endometrial cells, where its loss impairs implantation and decidualization. In cancer, IFITM3 interacts with MET to sustain AKT activation and drive osimertinib resistance in EGFR-mutant non-small cell lung cancer. Similarly, FARP1, ARHGEF39, and TIAM2 act as receptor tyrosine kinase effectors that promote Rac1-dependent motility downstream of MET. These findings highlight the importance of positive regulation in both physiological and pathological contexts. This article provides a comprehensive overview of GO:1902204, covering its definition, biological significance, key genes, regulatory mechanisms, disease associations, and experimental methods. By integrating authoritative QuickGO data with verified PubMed literature, we aim to support researchers in designing CRISPR-based models to dissect this pathway.
positive regulation of hepatocyte growth factor receptor signaling pathway At A Glance
| GO ID | GO:1902204 |
|---|---|
| GO term | positive regulation of hepatocyte growth factor receptor signaling pathway |
| Ontology | biological_process |
| Synonym | activation of Met signaling pathway, upregulation of HGF receptor signaling pathway |
| Major function | Enhances MET receptor tyrosine kinase signaling in response to HGF |
| Parent term | regulation of hepatocyte growth factor receptor signaling pathway |
| Related receptor | MET (hepatocyte growth factor receptor) |
| Key ligand | HGF (hepatocyte growth factor) |
| Downstream effectors | GRB2, AKT, Rac1, MAPK |
What Is GO:1902204?
GO:1902204 is a biological process term that encompasses any molecular event that enhances HGF receptor (MET) signaling. According to QuickGO, it is defined as any process that activates or increases the frequency, rate or extent of hepatocyte growth factor receptor signaling pathway. This includes mechanisms such as increased ligand binding, receptor stabilization, enhanced kinase activity, or amplified downstream signal transduction. Synonyms include activation of Met signaling pathway, upregulation of HGF receptor signaling, and positive regulation of HGF receptor signaling pathway.
Why Is positive regulation of hepatocyte growth factor receptor signaling pathway Important in Cell Biology?
Positive regulation of HGF receptor signaling is fundamental to tissue homeostasis and repair, but its dysregulation is a hallmark of many cancers and fibrotic diseases. Understanding the molecular players that enhance MET signaling can reveal therapeutic targets and biomarkers. For instance, GRB2-mediated potentiation of MET signaling is required for endometrial implantation, and its disruption leads to pregnancy failure. In cancer, IFITM3-MET interaction sustains AKT activation, conferring resistance to EGFR inhibitors. Thus, GO:1902204 provides a framework for studying how cells amplify MET signals in health and disease.
• Critical for embryonic development and organogenesis, as MET signaling drives cell proliferation and migration.
• Essential for tissue repair and regeneration, including liver and endometrial remodeling.
• Dysregulation contributes to cancer progression, metastasis, and drug resistance.
• Implicated in liver fibrosis, where HGF/MET signaling modulates fibrogenesis.
• Serves as a target for therapeutic intervention in MET-addicted cancers.
• Provides mechanistic insights into cell motility and invasion through Rac1 activation.
• Involved in immune regulation, as HGF/MET signaling can influence T cell exhaustion.
• Key for understanding resistance to targeted therapies like osimertinib.
• Enables identification of positive regulators via CRISPR screens.
• Facilitates development of precision medicine approaches for MET-driven diseases.
What Happens During positive regulation of hepatocyte growth factor receptor signaling pathway?
Ligand Binding and Receptor Activation
In simple terms: HGF binds to MET, turning the receptor on.
The hepatocyte growth factor (HGF) binds to the extracellular domain of MET, inducing receptor dimerization and autophosphorylation. This activation is the first step in the signaling cascade and is subject to positive regulation by factors that increase HGF availability or MET sensitivity. For example, in liver fibrosis, hepatocyte-specific NRP-1 knockout alters HGF/C-Met interaction, affecting fibrosis progression.
Adaptor Protein Recruitment
In simple terms: Adaptor proteins like GRB2 dock onto MET to relay the signal.
Upon activation, MET recruits adaptor proteins such as GRB2, which binds to phosphorylated tyrosine residues on MET. GRB2 is a positive regulator of MET signaling; its loss in endometrial cells impairs implantation and decidualization, demonstrating its essential role. GRB2 then activates downstream pathways including RAS-MAPK and PI3K-AKT.
Downstream Effector Activation
In simple terms: Signals are passed to effectors like AKT and Rac1 to drive cellular responses.
Positive regulation of MET signaling involves activation of downstream effectors. IFITM3 interacts with MET to drive AKT pathway activation, contributing to osimertinib resistance in EGFR-mutant NSCLC. Additionally, FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility downstream of MET.
Amplification and Crosstalk
In simple terms: Other signals can boost MET signaling, making the response stronger.
Positive regulation can occur through crosstalk with other pathways. For instance, hypoxia synergizes with HGF to promote tumor cell invasiveness, enhancing MET signaling. Diet-derived galactose reprograms hepatocytes to modulate immune responses, potentially influencing HGF/MET signaling. These examples illustrate how environmental and metabolic factors can positively regulate MET signaling.
Key Genes Involved in GO:1902204 positive regulation of hepatocyte growth factor receptor signaling pathway
The following genes and proteins are key players in the positive regulation of hepatocyte growth factor receptor signaling pathway, based on verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| HGF | Ligand that activates MET receptor | Essential for MET activation; studied in tissue repair and cancer |
| MET | Receptor tyrosine kinase | Central to pathway; mutations and overexpression drive cancers |
| GRB2 | Adaptor protein linking MET to downstream pathways | Positive regulator; required for implantation and decidualization |
| IFITM3 | Interacts with MET to enhance AKT signaling | Drives osimertinib resistance in EGFR-mutant NSCLC |
| FARP1 | Rac1 guanine nucleotide exchange factor | Effector for MET-driven cell motility |
| ARHGEF39 | Rac1 guanine nucleotide exchange factor | Effector for MET-driven cell motility |
| TIAM2 | Rac1 guanine nucleotide exchange factor | Effector for MET-driven cell motility |
| NRP1 | Neuropilin-1, modulates HGF/C-Met interaction | Influences liver fibrosis progression |
| AKT1 | Serine/threonine kinase downstream of MET | Mediates survival and resistance |
| RAC1 | Rho GTPase regulating motility | Downstream effector of MET signaling |
| IRF4 | Transcription factor promoting T cell exhaustion | May intersect with HGF/MET in immune regulation |
| NR3C1 | Glucocorticoid receptor | Regulates CD8 T cell differentiation; potential crosstalk |
| HIF1A | Hypoxia-inducible factor | Synergizes with HGF to promote invasiveness |
| GALM | Galactose mutarotase | Diet-derived galactose metabolism in hepatocytes |
| GALK1 | Galactokinase | Galactose metabolism affecting hepatocyte function |
| GALE | UDP-galactose-4-epimerase | Galactose metabolism in hepatocytes |
| GALT | Galactose-1-phosphate uridylyltransferase | Galactose metabolism in hepatocytes |
How Is positive regulation of hepatocyte growth factor receptor signaling pathway Regulated?
Positive regulation of HGF receptor signaling is controlled at multiple levels. Ligand availability is a primary determinant; HGF expression can be induced by hypoxia and inflammatory cytokines. Receptor levels and activity are modulated by endocytosis, degradation, and phosphatases. Adaptor proteins like GRB2 positively regulate the pathway by facilitating downstream signaling. Additionally, crosstalk with other signaling cascades, such as glucocorticoid receptor signaling, can influence MET activity. Metabolic factors, including diet-derived galactose, can reprogram hepatocytes and potentially affect HGF/MET signaling.
positive regulation of hepatocyte growth factor receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MET | Non-small cell lung cancer, drug resistance | Point mutation knock-in (e.g., MET exon 14 skipping) in NSCLC cell lines |
| GRB2 | Endometrial implantation failure | Hepatocyte-specific or endometrial knockout mice |
| NRP1 | Liver fibrosis | Hepatocyte-specific NRP-1 knockout mice |
| IFITM3 | Osimertinib resistance in EGFR-mutant NSCLC | Overexpression and knockout in EGFR-mutant cell lines |
| FARP1/ARHGEF39/TIAM2 | Lung adenocarcinoma metastasis | Knockout in lung adenocarcinoma cell lines |
Cancer Progression and Drug Resistance
Aberrant positive regulation of MET signaling drives tumorigenesis, metastasis, and resistance to targeted therapies. In EGFR-mutant non-small cell lung cancer, IFITM3 interacts with MET to sustain AKT activation, leading to osimertinib resistance. HGF and hypoxia synergistically promote tumor cell invasiveness, enhancing metastatic potential. Rac1 effectors such as FARP1, ARHGEF39, and TIAM2 are essential for MET-driven motility in lung adenocarcinoma.
Liver Fibrosis
HGF/MET signaling plays a dual role in liver fibrosis. In hepatocyte-specific NRP-1 knockout mice, disruption of the HGF/C-Met interaction alters fibrosis progression, indicating that positive regulation of MET signaling can modulate fibrogenesis. Understanding these mechanisms may lead to therapies for chronic liver disease.
Reproductive Disorders
GRB2-mediated positive regulation of MET signaling is critical for endometrial implantation and decidualization. Loss of GRB2 impairs these processes, suggesting that dysregulation of GO:1902204 may contribute to infertility.
Immune Regulation and T Cell Exhaustion
HGF/MET signaling can influence immune responses. Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity, potentially through modulation of HGF/MET signaling. Glucocorticoid signaling regulates CD8+ T cell differentiation and dysfunction, which may intersect with MET pathways. IRF4 promotes CD8+ T cell exhaustion during chronic infection, and its interplay with MET signaling warrants further study.
From positive regulation of hepatocyte growth factor receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of GRB2 impair MET signaling in endometrium? | GRB2 knockout mice or endometrial cell lines |
| Does IFITM3-MET interaction drive osimertinib resistance? | IFITM3 overexpression and knockout in EGFR-mutant NSCLC cells |
| How does NRP-1 modulate HGF/C-Met in liver fibrosis? | Hepatocyte-specific NRP-1 knockout mice |
| Do FARP1, ARHGEF39, and TIAM2 regulate Rac1-dependent motility? | Knockout of these genes in lung adenocarcinoma cells |
| Does hypoxia synergize with HGF to promote invasion? | Hypoxia chamber experiments with HGF treatment in cancer cells |
| Does diet-derived galactose affect hepatocyte-immune crosstalk? | Galactose-fed mice and hepatocyte-specific knockout models |
How to Study the positive regulation of hepatocyte growth factor receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Loss-of-function effects on MET signaling | Identify positive regulators like GRB2 |
| Phosphoproteomics | Phosphorylation changes in MET and downstream targets | Quantify AKT activation by IFITM3 |
| Live-cell imaging | Receptor dynamics and localization | Study NRP-1 modulation of HGF/C-Met |
| RNA-seq | Transcriptional changes | Analyze galactose effects on hepatocytes |
| Co-immunoprecipitation | Protein-protein interactions | Detect IFITM3-MET interaction |
| Rac1 activity assay | GTPase activation | Measure FARP1/ARHGEF39/TIAM2 function |
| Hypoxia chamber assays | Invasiveness under low oxygen | Study synergy with HGF |
| Flow cytometry | T cell exhaustion markers | Assess immune modulation by HGF/MET |
CRISPR Knockout Screens
Genome-wide CRISPR knockout screens can identify positive regulators of MET signaling. For example, loss of GRB2 was shown to impair MET signaling in endometrial cells. Similarly, screens in lung adenocarcinoma cells identified FARP1, ARHGEF39, and TIAM2 as essential for Rac1-dependent motility downstream of MET.
Phosphoproteomics
Phosphoproteomic profiling can quantify changes in MET autophosphorylation and downstream phosphorylation events upon positive regulation. This approach can reveal how IFITM3 enhances AKT activation in osimertinib-resistant cells.
Live-Cell Imaging
Live-cell imaging of fluorescently tagged MET and effectors can visualize receptor internalization, trafficking, and downstream signaling dynamics. This is useful for studying how NRP-1 modulates HGF/C-Met interaction in liver fibrosis.
RNA Sequencing
RNA-seq can identify transcriptional changes induced by positive regulators of MET signaling. For instance, galactose metabolism in hepatocytes alters gene expression programs that may influence T cell exhaustion.
How CRISPR Can Be Used to Study GO:1902204 positive regulation of hepatocyte growth factor receptor signaling pathway
Knockout
CRISPR knockout of positive regulators such as GRB2, FARP1, ARHGEF39, or TIAM2 can abolish MET signaling and downstream phenotypes. For example, GRB2 knockout in endometrial cells impairs implantation and decidualization. Knockout of Rac1 effectors reduces cell motility in lung adenocarcinoma.
Point Mutation
Point mutations in MET, such as kinase domain mutations or exon 14 skipping, can be introduced using CRISPR to model drug resistance. These models help study how specific mutations affect positive regulation of MET signaling and response to inhibitors.
Knock-in
Knock-in of tagged MET or effector proteins (e.g., GFP-MET) allows real-time visualization of receptor trafficking and signaling dynamics. This approach can be used to study NRP-1 modulation of HGF/C-Met in liver fibrosis.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression can elevate levels of positive regulators like IFITM3 to assess their impact on MET signaling and drug resistance. Overexpression of IFITM3 in EGFR-mutant NSCLC cells enhances AKT activation and osimertinib resistance.
How EDITGENE Supports positive regulation of hepatocyte growth factor receptor signaling pathway Research
Researchers studying positive regulation of hepatocyte growth factor receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in enhancing MET signaling. EDITGENE provides comprehensive CRISPR-based services to interrogate gene function, from knockout to precise point mutations, enabling mechanistic studies and therapeutic target validation.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of hepatocyte growth factor receptor signaling pathway research.
Frequently Asked Questions About positive regulation of hepatocyte growth factor receptor signaling pathway
What is GO:1902204?
GO:1902204 is a Gene Ontology term for any process that activates or increases the frequency, rate or extent of hepatocyte growth factor receptor signaling pathway, also known as MET signaling.
What genes are involved in positive regulation of hepatocyte growth factor receptor signaling?
Key genes include HGF, MET, GRB2, IFITM3, FARP1, ARHGEF39, TIAM2, and NRP1, among others.
How is positive regulation of MET signaling studied?
Researchers use CRISPR knockout screens, phosphoproteomics, live-cell imaging, and RNA-seq to study this pathway.
What diseases are associated with dysregulated MET signaling?
Cancers such as non-small cell lung cancer, liver fibrosis, and reproductive disorders like implantation failure are linked to aberrant MET signaling.
What is the role of GRB2 in MET signaling?
GRB2 is an adaptor protein that positively regulates MET signaling by linking the receptor to downstream pathways; its loss impairs implantation and decidualization.
How does IFITM3 contribute to osimertinib resistance?
IFITM3 interacts with MET to enhance AKT pathway activation, driving resistance to osimertinib in EGFR-mutant non-small cell lung cancer.
Can CRISPR be used to model MET signaling?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used to study MET signaling and its regulators.
What is the role of NRP-1 in HGF/C-Met signaling?
Neuropilin-1 (NRP-1) modulates HGF/C-Met interaction, and its hepatocyte-specific knockout alters liver fibrosis progression.
Which Rac1 effectors are involved in MET-driven motility?
FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility downstream of MET.
How does hypoxia affect HGF/MET signaling?
Hypoxia synergizes with HGF to promote tumor cell invasiveness, enhancing MET signaling.
Conclusion
GO:1902204, positive regulation of hepatocyte growth factor receptor signaling pathway, is a critical biological process that amplifies MET signaling in development, tissue repair, and disease. Key positive regulators such as GRB2, IFITM3, and Rac1 effectors have been identified through CRISPR screens and biochemical studies. Dysregulation of this pathway contributes to cancer, fibrosis, and reproductive disorders, making it a prime therapeutic target. EDITGENE's comprehensive CRISPR services empower researchers to dissect these mechanisms and accelerate drug discovery.
References
- 1. Tran DN et al.. 2025. GRB2 regulation of essential signaling pathways in the endometrium is critical for implantation and decidualization.. Nat Commun 16(1):2192 PMID: 40038241
- 2. Du X et al.. 2025. Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity.. Nat Cell Biol 27(8):1357-1366 PMID: 40781141
- 3. Acharya N et al.. 2020. Endogenous Glucocorticoid Signaling Regulates CD8(+) T Cell Differentiation and Development of Dysfunction in the Tumor Microenvironment.. Immunity 53(3):658-671.e6 PMID: 32937153
- 4. Ibusuki R et al.. 2025. IFITM3-MET interaction drives osimertinib resistance through AKT pathway activation in EGFR-mutant non-small cell lung cancer.. Mol Cancer 24(1):272 PMID: 41152910
- 5. Man K et al.. 2017. Transcription Factor IRF4 Promotes CD8(+) T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection.. Immunity 47(6):1129-1141.e5 PMID: 29246443
- 6. Ding H et al.. 2025. Interaction of neuropilin-1 and hepatocyte growth factor/C-Met pathway in liver fibrosis progression in hepatocyte-specific NRP-1 knockout mice.. J Gastroenterol 60(8):1000-1013 PMID: 40419692
- 7. Cooke M et al.. 2021. FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma.. Cell Rep 37(5):109905 PMID: 34731623
- 8. Lee YH et al.. 2014. Synergistic signaling of tumor cell invasiveness by hepatocyte growth factor and hypoxia.. J Biol Chem 289(30):20448-61 PMID: 24914205
