GO:0048012 hepatocyte growth factor receptor signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0048012 (hepatocyte growth factor receptor signaling pathway) describes the molecular signal relay triggered when hepatocyte growth factor (HGF) binds its receptor MET, ending in regulation of downstream cellular processes such as transcription.
• MET is a receptor tyrosine kinase; ligand binding activates its kinase domain and drives autophosphorylation, creating docking sites for adaptor proteins.
• The pathway controls proliferation, survival, migration, morphogenesis and immune cell functions, and is a validated therapeutic target in multiple cancers.
• Dysregulated HGF/MET signaling is implicated in renal cell carcinoma, angiogenesis, cancer progression and biomarker discovery.
• HGF/MET signaling also participates in non-cancer biology, including infectious disease responses and diabetes-associated neuroinflammation.
• CRISPR-based knockout, point-mutation, knock-in and overexpression models enable causal dissection of HGF/MET pathway genes.
Description
GO:0048012, the hepatocyte growth factor receptor signaling pathway, is the biological process initiated when the ligand hepatocyte growth factor (HGF) binds to its receptor, the MET receptor tyrosine kinase. The pathway converts an extracellular ligand cue into intracellular signals that ultimately regulate transcription and other downstream cellular processes. Because MET is a receptor tyrosine kinase, activation involves autophosphorylation and recruitment of signaling adaptors, which is why the pathway is often called the Met signaling pathway or HGF receptor signaling pathway. Researchers study GO:0048012 because it sits at the intersection of normal tissue morphogenesis and major human diseases, especially cancer. The pathway is also relevant to immune cell modulation, angiogenesis and infectious disease biology, making it a broad research topic rather than a cancer-only process. Understanding its molecular steps helps explain how cells interpret HGF gradients and how pathway mutations or overexpression can drive pathological outcomes.
hepatocyte growth factor receptor signaling pathway At A Glance
| GO ID | GO:0048012 |
|---|---|
| GO term | hepatocyte growth factor receptor signaling pathway |
| Ontology | biological_process |
| Synonym | HGF receptor signaling pathway; HGF receptor signalling pathway; Met signaling pathway |
| Definition | The series of molecular signals initiated by a ligand binding to a hepatocyte growth factor receptor, and ending with the regulation of a downstream cellular process, e.g. transcription. |
| Major function | Transduces HGF/MET ligand-receptor signals into cellular responses such as proliferation, survival, migration and transcription. |
| Key receptor | MET (c-Met), a receptor tyrosine kinase. |
| Key ligand | Hepatocyte growth factor (HGF). |
| Disease relevance | Cancer, angiogenesis, renal cell carcinoma, infectious disease and neuroinflammation. |
What Is GO:0048012?
In simple terms, GO:0048012 is the series of molecular signals that starts when hepatocyte growth factor binds a hepatocyte growth factor receptor and ends with regulation of a downstream cellular process, such as transcription. The receptor involved is MET, a receptor tyrosine kinase, and the pathway is also known as HGF receptor signaling pathway or Met signaling pathway. The definition emphasizes a ligand-initiated signal relay rather than a single molecular event, so the term covers receptor activation, intracellular signal transduction and the resulting changes in cell behavior or gene expression.
Why Is hepatocyte growth factor receptor signaling pathway Important in Cell Biology?
GO:0048012 is important because HGF/MET signaling is one of the most frequently dysregulated pathways in human cancer and is also essential for normal tissue repair, immune regulation and angiogenesis. The pathway provides a clear example of how a receptor tyrosine kinase converts a ligand signal into transcriptional and cytoskeletal responses, making it a model system for signal transduction research. Its clinical relevance spans renal cell carcinoma, biomarker discovery and therapeutic targeting, while emerging work links it to infectious disease and diabetes-associated neuroinflammation.
• Controls fundamental cell behaviors including proliferation, survival, migration and morphogenesis.
• Is a validated therapeutic target in renal cell carcinoma and other cancers.
• Regulates angiogenesis, making it relevant to vascular biology and anti-angiogenic strategies.
• Serves as a source of cancer biomarkers through HGF/MET pathway profiling.
• Modulates immune cell functions, linking the pathway to immunology.
• Participates in host responses during infectious diseases.
• Is implicated in diabetes-associated hippocampal neuroinflammation.
• Provides a paradigm for receptor tyrosine kinase signal transduction and PI3-kinase activation.
• Offers multiple druggable nodes, from ligand binding to downstream kinase cascades.
• Enables CRISPR-based causal genetics of pathway components in disease models.
What Happens During hepatocyte growth factor receptor signaling pathway?
Ligand binding and receptor activation
In simple terms: HGF docks onto the MET receptor and switches it on.
The pathway begins when hepatocyte growth factor binds the MET receptor tyrosine kinase, triggering receptor activation. MET is a receptor tyrosine kinase, and ligand binding initiates the signaling cascade that defines GO:0048012. This step is the defining event of the GO term because the definition specifies a signal initiated by ligand binding to a hepatocyte growth factor receptor.
Receptor autophosphorylation and adaptor recruitment
In simple terms: The activated receptor phosphorylates itself and attracts signaling proteins.
Activated MET undergoes autophosphorylation, which creates docking sites for downstream adaptor and effector proteins. This phosphorylation-dependent step is a hallmark of receptor tyrosine kinase signaling and is required for propagation of the HGF signal. The recruitment of signaling molecules at the receptor is what converts the extracellular ligand cue into an intracellular biochemical signal.
Downstream kinase cascades including PI3-kinase
In simple terms: The signal travels through enzymes such as PI3-kinase inside the cell.
Signal transduction by the HGF receptor c-met includes activation of phosphatidylinositol 3-kinase, demonstrating that the pathway engages lipid kinase signaling in addition to other cascades. These downstream events amplify and diversify the initial receptor signal. The pathway is described as ending with regulation of a downstream cellular process, consistent with these intracellular relays.
Regulation of transcription and cellular responses
In simple terms: The signal reaches the nucleus and changes which genes are active.
The GO definition states that the pathway ends with regulation of a downstream cellular process, for example transcription. Through this output, HGF/MET signaling influences diverse cellular functions, including immune cell functions and cancer progression. The transcriptional consequences help explain why the pathway has broad roles in physiology and disease.
Key Genes Involved in GO:0048012 hepatocyte growth factor receptor signaling pathway
The following genes and proteins are central to the hepatocyte growth factor receptor signaling pathway (GO:0048012) and are commonly studied in pathway research.
| Gene | Major Role | Research Relevance |
|---|---|---|
| HGF | Ligand that binds and activates the MET receptor | Pathway initiation; physiology and infectious disease |
| MET | Receptor tyrosine kinase that defines the pathway | Core receptor; cancer targeting and biomarker studies |
| PIK3CA | Catalytic subunit linked to PI3-kinase activation downstream of c-met | Downstream lipid kinase signaling |
| PIK3R1 | Regulatory subunit of PI3-kinase implicated in c-met signal transduction | Downstream signaling regulation |
| KLK8 | Protease implicated in KLK8/HGF/Met signaling in neuroinflammation | Diabetes-associated hippocampal neuroinflammation |
| VEGFA | Angiogenic factor connected to HGF/c-Met-driven angiogenesis | Anti-angiogenic targeting |
| EGFR | Receptor tyrosine kinase often studied alongside MET in cancer signaling | Pathway crosstalk in cancer |
| KRAS | Downstream oncogene frequently co-analyzed with MET pathway alterations | Cancer progression and therapy resistance |
| BRAF | Kinase in oncogenic signaling networks intersecting MET biology | Cancer targeting and biomarker discovery |
| STAT3 | Transcription factor activated by cytokine and growth factor signaling including HGF/MET | Immune cell function and transcription output |
| AKT1 | Kinase downstream of PI3-kinase in growth factor signaling | Survival signaling downstream of c-met |
| MAPK1 | Kinase in MAPK cascades downstream of receptor tyrosine kinases | Proliferation signaling |
| MAPK3 | Kinase in MAPK cascades downstream of receptor tyrosine kinases | Proliferation signaling |
| CDH1 | Adhesion protein relevant to MET-driven morphogenesis and migration | Cell migration and morphogenesis |
| MMP9 | Matrix metalloproteinase associated with invasion in HGF/MET-driven cancer | Cancer progression and biomarker studies |
| CXCL8 | Cytokine linked to immune modulation by HGF/MET signaling | Immune cell function |
| IL6 | Cytokine connected to HGF/MET-related immune and inflammatory responses | Immune modulation and inflammation |
How Is hepatocyte growth factor receptor signaling pathway Regulated?
HGF/MET signaling is regulated at multiple levels, including ligand availability, receptor activation and downstream kinase cascades. The pathway engages phosphatidylinositol 3-kinase, showing that downstream lipid kinase activity is part of its regulatory architecture. In immune cells, HGF/MET signaling modulates diverse functions, indicating context-dependent regulation. In disease settings such as cancer, pathway activity is often dysregulated, which is why it is targeted therapeutically. Emerging evidence also links KLK8/HGF/Met signaling to diabetes-associated hippocampal neuroinflammation, suggesting that pathological contexts can reshape pathway regulation.
hepatocyte growth factor receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MET | Renal cell carcinoma and cancer progression | Cancer cell line knockout and point-mutation models |
| HGF | Infectious disease and immune modulation | Ligand overexpression and knockout models |
| KLK8 | Diabetes-associated hippocampal neuroinflammation | Mouse neuroinflammation models with KLK8 perturbation |
| VEGFA | Angiogenesis | Endothelial cell models with pathway inhibition |
| PIK3CA | Downstream PI3-kinase signaling in c-met transduction | Isogenic knock-in and knockout cell lines |
Cancer and renal cell carcinoma
The HGF/MET pathway is a well-recognized therapeutic target in cancer, including renal cell carcinoma. Targeting the hepatocyte growth factor/c-Met signaling pathway has been proposed as a strategy in renal cell carcinoma, reflecting the pathway's role in tumor biology. HGF/MET signaling is also studied in cancer progression and biomarker discovery, underscoring its clinical importance.
Angiogenesis and vascular biology
The hepatocyte growth factor/c-Met signaling pathway has been described as a therapeutic target to inhibit angiogenesis. This links GO:0048012 to vascular processes and to anti-angiogenic treatment strategies. The pathway therefore matters beyond tumor cells themselves, influencing the tumor microenvironment.
Infectious disease and immune modulation
HGF has roles in physiology and infectious diseases, connecting the pathway to host-pathogen biology. The HGF-MET receptor tyrosine kinase signaling pathway also has diverse roles in modulating immune cell functions. These findings broaden the disease relevance of GO:0048012 beyond oncology.
Diabetes-associated neuroinflammation
KLK8/HGF/Met signaling has been reported to mediate diabetes-associated hippocampal neuroinflammation in male mice. This indicates that the pathway can contribute to neuroinflammatory processes in metabolic disease contexts. It highlights the value of studying GO:0048012 in neurological and metabolic models.
From hepatocyte growth factor receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of MET abolish HGF-induced transcription? | MET knockout cell line |
| Does a specific MET kinase-domain mutation alter downstream PI3-kinase activation? | Point-mutation knock-in of MET |
| Can a tagged MET receptor be used to map interacting proteins? | Tagged knock-in of MET |
| Does HGF overexpression drive migration or angiogenesis phenotypes? | HGF overexpression model |
| Which downstream genes mediate HGF/MET transcriptional output? | Pathway-focused CRISPR library screening |
| Does KLK8/HGF/Met signaling contribute to neuroinflammation? | KLK8 knockout or overexpression in neuroinflammation models |
How to Study the hepatocyte growth factor receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptional output of pathway activation | HGF-stimulated vs. control cells |
| Phosphoproteomics | Receptor and downstream phosphorylation events | MET activation status |
| PI3-kinase activity assay | Lipid kinase activation downstream of c-met | Signal transduction studies |
| CRISPR library screening | Genes required for pathway phenotypes | Target discovery in cancer models |
| Western blot | Protein expression and phosphorylation | Pathway validation |
| Immunofluorescence imaging | Subcellular localization of pathway components | Receptor trafficking and morphology |
| Biomarker profiling | HGF/MET pathway-associated biomarkers | Cancer biomarker discovery |
| In vivo tumor models | Pathway contribution to tumor growth | Therapeutic target evaluation |
Transcriptomic profiling of pathway output
Because GO:0048012 ends with regulation of downstream cellular processes such as transcription, RNA-seq is a natural method to measure pathway output after HGF stimulation or MET perturbation. Comparing wild-type and MET-mutant cells reveals transcriptional programs controlled by the pathway. This approach connects receptor activation to gene expression changes relevant to cancer and immune biology.
Phosphoproteomics and kinase signaling assays
Receptor autophosphorylation and downstream kinase activation are central to HGF/MET signaling, so phosphoproteomic and kinase assays are used to monitor pathway activity. PI3-kinase activation downstream of c-met can be assessed to confirm signaling engagement. These methods help define which nodes are active in a given disease context.
CRISPR screening and functional genomics
CRISPR library screening enables systematic identification of genes required for HGF/MET pathway activity or for pathway-driven phenotypes. Such screens can nominate therapeutic targets within the pathway. Functional genomics complements biochemical assays by linking genes to pathway output.
Disease-relevant in vivo and cell models
Pathway research uses cancer, immune, endothelial and neuroinflammation models to capture the diverse roles of HGF/MET signaling. Renal cell carcinoma models are particularly relevant given the pathway's established role there. Infectious disease and immune models address the broader physiology of HGF.
How CRISPR Can Be Used to Study GO:0048012 hepatocyte growth factor receptor signaling pathway
Knockout
CRISPR knockout of MET or HGF provides a clean loss-of-function test of whether GO:0048012 is required for a given cellular response. Knockout models are useful for validating pathway dependency in cancer and immune cells. They also help distinguish pathway-specific effects from compensatory signaling.
Point Mutation
Point-mutation models can interrogate specific phosphorylation sites or kinase-domain residues in MET to determine which molecular events drive downstream signaling. Such models are valuable for dissecting PI3-kinase activation and other downstream cascades. They allow causal testing of individual pathway nodes without deleting the entire gene.
Knock-in
Knock-in of tags or reporter sequences at the MET or HGF locus enables tracking of pathway components in live cells. Tagged knock-in models support interaction proteomics and localization studies of the receptor. They are also useful for monitoring pathway activation in disease-relevant contexts.
Overexpression
Overexpression of HGF or MET can model pathway hyperactivation observed in cancer and other diseases. These models help test whether increased pathway flux is sufficient to drive proliferation, migration or angiogenesis. They complement knockout studies by probing gain-of-function phenotypes.
How EDITGENE Supports hepatocyte growth factor receptor signaling pathway Research
Researchers studying hepatocyte growth factor receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in pathway output, disease phenotypes or therapeutic response. EDITGENE provides CRISPR-based cell model services that allow precise perturbation of HGF/MET pathway components, from complete knockout to subtle point mutations and tagged knock-ins.
Contact EDITGENE today to design your custom CRISPR model for hepatocyte growth factor receptor signaling pathway research.
Frequently Asked Questions About hepatocyte growth factor receptor signaling pathway
What is GO:0048012 hepatocyte growth factor receptor signaling pathway?
GO:0048012 is the biological process in which hepatocyte growth factor binds its receptor and initiates a signal relay that ends with regulation of a downstream cellular process such as transcription.
What genes are involved in hepatocyte growth factor receptor signaling pathway?
Key genes include HGF, MET, PIK3CA, PIK3R1, KLK8 and downstream signaling genes such as AKT1 and MAPK1.
What is the receptor in the HGF signaling pathway?
The receptor is MET, also known as c-Met, a receptor tyrosine kinase.
Why is the HGF/MET pathway important in cancer?
It is a therapeutic target in cancers including renal cell carcinoma and is linked to cancer progression and biomarker discovery.
How is HGF/MET signaling regulated?
It is regulated through ligand availability, receptor autophosphorylation and downstream cascades including PI3-kinase activation.
Does HGF/MET signaling affect immune cells?
Yes, the HGF-MET receptor tyrosine kinase signaling pathway has diverse roles in modulating immune cell functions.
Is the HGF/MET pathway involved in angiogenesis?
Yes, the hepatocyte growth factor/c-Met signaling pathway has been studied as a therapeutic target to inhibit angiogenesis.
What diseases are linked to HGF/MET signaling?
Cancer, renal cell carcinoma, infectious disease, immune modulation and diabetes-associated hippocampal neuroinflammation have been linked to the pathway.
How do researchers study GO:0048012?
They use RNA-seq, phosphoproteomics, PI3-kinase assays, CRISPR screening and disease-relevant cell or animal models.
Can CRISPR be used to study the HGF/MET pathway?
Yes, CRISPR knockout, point mutation, knock-in and overexpression models allow causal dissection of pathway genes.
Conclusion
GO:0048012, the hepatocyte growth factor receptor signaling pathway, is a central biological process that converts HGF binding to MET into transcriptional and cellular responses. Its roles in cancer, angiogenesis, immune modulation, infectious disease and neuroinflammation make it a high-value research and therapeutic topic. CRISPR-based models provide a rigorous way to test causality within this pathway and to translate pathway biology into disease insights.
References
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- 2. Xu DH et al.. 2025. KLK8/HGF/Met signaling pathway mediates diabetes-associated hippocampal neuroinflammation in male mice.. Theranostics 15(13):6290-6312 PMID: 40521191
- 3. Harshman LC et al.. 2013. Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma.. Cancer J 19(4):316-23 PMID: 23867513
- 4. You WK et al.. 2008. The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis.. BMB Rep 41(12):833-9 PMID: 19123972
- 5. Imamura R et al.. 2017. Hepatocyte growth factor in physiology and infectious diseases.. Cytokine 98:97-106 PMID: 28094206
- 6. De Silva DM et al.. 2017. Targeting the hepatocyte growth factor/Met pathway in cancer.. Biochem Soc Trans 45(4):855-870 PMID: 28673936
- 7. Matsumoto K et al.. 2017. Hepatocyte growth factor/MET in cancer progression and biomarker discovery.. Cancer Sci 108(3):296-307 PMID: 28064454
- 8. Cantley LG et al.. 1995. Signal transduction by the hepatocyte growth factor receptor, c-met. Activation of the phosphatidylinositol 3-kinase.. J Am Soc Nephrol 5(11):1872-81 PMID: 7620084
