GO:1902203 negative 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:1902203 describes any process that stops, prevents or reduces the frequency, rate or extent of hepatocyte growth factor receptor (MET) signaling.
• The term is a biological_process ontology annotation and includes synonyms such as negative regulation of Met signaling pathway and inhibition of HGF receptor signaling pathway.
• Negative regulation of MET signaling is critical for controlling liver regeneration, fibrosis, and cancer progression [5, 1, 4].
• Key negative regulators include CXCL13, Cbl-family E3 ubiquitin ligases, and Ninjurin2, which modulate MET downstream effectors [5, 7, 1].
• Dysregulation of this process is implicated in hepatocellular carcinoma, breast cancer, prostate cancer, and neuroblastoma [4, 2, 8].
• CRISPR knockout, point mutation, knock-in, and overexpression models are essential to dissect causal roles of negative regulators in MET signaling [7, 5].
Description
The hepatocyte growth factor (HGF) receptor, also known as MET, is a receptor tyrosine kinase that controls cell proliferation, survival, migration, and morphogenesis. Its signaling must be tightly controlled because excessive or prolonged MET activation drives tumorigenesis and tissue fibrosis [1, 4]. The Gene Ontology term GO:1902203, negative regulation of hepatocyte growth factor receptor signaling pathway, captures the biological processes that attenuate or terminate MET signaling. This term is essential for researchers studying liver regeneration, cancer biology, and developmental signaling because it defines the molecular brakes that prevent aberrant HGF/MET activity [5, 7]. Understanding these negative regulators provides mechanistic insights into diseases where MET signaling is hyperactive, such as hepatocellular carcinoma and neuroblastoma [8, 4].
negative regulation of hepatocyte growth factor receptor signaling pathway At A Glance
| GO ID | GO:1902203 |
|---|---|
| GO term | negative regulation of hepatocyte growth factor receptor signaling pathway |
| Ontology | biological_process |
| Synonym | down regulation of Met signaling pathway; inhibition of HGF receptor signaling pathway; negative regulation of HGF receptor signalling pathway |
| Major function | Attenuation or termination of HGF/MET receptor tyrosine kinase signaling |
| Key negative regulators | CXCL13, Cbl E3 ubiquitin ligases, Ninjurin2 |
| Associated diseases | Liver fibrosis, hepatocellular carcinoma, breast cancer, prostate cancer, neuroblastoma |
| Research methods | CRISPR KO/point mutation/knock-in/overexpression, RNA-seq, proteomics, ubiquitination assays |
What Is GO:1902203?
GO:1902203 is defined as any process that stops, prevents or reduces the frequency, rate or extent of the hepatocyte growth factor receptor signaling pathway. In practical terms, it encompasses molecular events that dampen or shut down signal transduction initiated by HGF binding to its receptor MET, including receptor ubiquitination, dephosphorylation, internalization, and downstream feedback inhibition [7, 5].
Why Is negative regulation of hepatocyte growth factor receptor signaling pathway Important in Cell Biology?
Negative regulation of HGF receptor signaling is a fundamental homeostatic mechanism that prevents uncontrolled cell growth and tissue remodeling. In the liver, CXCL13 suppresses liver regeneration through negative regulation of HGF signaling, highlighting its physiological role in tissue repair. In cancer, loss of negative regulators such as Cbl E3 ubiquitin ligases leads to sustained MET activation, promoting tumor progression and metastasis [7, 4]. Therefore, understanding GO:1902203 is critical for developing therapeutic strategies that restore negative control of MET signaling in disease [1, 8].
• Controls liver regeneration by limiting HGF-driven hepatocyte proliferation.
• Prevents fibrosis by modulating hepatic stellate cell activation through MET-related pathways.
• Suppresses tumorigenesis by terminating oncogenic MET signaling in cancers [4, 8].
• Regulates cell migration and metabolic reprogramming in breast cancer.
• Involves ubiquitination-dependent receptor degradation via Cbl family E3 ligases.
• Provides therapeutic targets for hepatocellular carcinoma and neuroblastoma [8, 4].
• Essential for developmental morphogenesis where MET signaling must be spatially and temporally restricted.
• Serves as a paradigm for negative regulation of receptor tyrosine kinases.
What Happens During negative regulation of hepatocyte growth factor receptor signaling pathway?
Receptor ubiquitination and degradation
In simple terms: The activated MET receptor gets tagged with ubiquitin molecules, which marks it for destruction inside the cell.
Upon HGF stimulation, the E3 ubiquitin ligase Cbl binds to phosphorylated MET and catalyzes its ubiquitination, leading to receptor internalization and degradation. This process is a major mechanism for negative regulation of HGF receptor signaling and prevents sustained downstream signaling.
Feedback inhibition by downstream effectors
In simple terms: Signals turned on by MET can loop back to shut themselves off.
Activation of MET triggers downstream kinases such as ERK and AKT, which can phosphorylate and inhibit upstream components of the pathway, including MET itself or its adaptor proteins, thereby reducing signal duration [5, 7]. This negative feedback is essential for limiting regenerative responses in the liver.
CXCL13-mediated suppression of HGF signaling
In simple terms: A chemokine called CXCL13 acts as a brake on liver regeneration by blocking HGF signals.
CXCL13 suppresses liver regeneration through the negative regulation of HGF signaling, as demonstrated in experimental models. This chemokine interferes with MET downstream pathways, reducing hepatocyte proliferation and preventing excessive tissue growth.
Modulation by Ninjurin2 and IGF1R/EGR1/PDGF-BB axis
In simple terms: A protein called Ninjurin2 in hepatocytes promotes fibrosis by influencing growth factor signals that intersect with MET.
Hepatocyte Ninjurin2 promotes hepatic stellate cell activation and liver fibrosis through the IGF1R/EGR1/PDGF-BB signaling pathway, which can indirectly affect HGF/MET signaling balance. This illustrates how negative regulation of HGF receptor signaling is integrated with other growth factor networks in liver disease.
Key Genes Involved in GO:1902203 negative regulation of hepatocyte growth factor receptor signaling pathway
The following genes and proteins are experimentally implicated in the negative regulation of hepatocyte growth factor receptor signaling pathway.
| Gene | Major Role | Research Relevance |
|---|---|---|
| MET | Receptor tyrosine kinase for HGF; target of negative regulation | Central to pathway; mutations cause cancer [3, 4] |
| HGF | Ligand that activates MET | Initiates signaling; negative regulators oppose its effects [3, 5] |
| CBL | E3 ubiquitin ligase that ubiquitinates MET | Key negative regulator; loss leads to sustained MET signaling |
| CXCL13 | Chemokine that suppresses HGF signaling | Inhibits liver regeneration; negative regulator in vivo |
| NINJ2 | Ninjurin2; promotes fibrosis via IGF1R/EGR1/PDGF-BB | Indirectly modulates HGF/MET balance in liver |
| IGF1R | Insulin-like growth factor 1 receptor | Cross-talks with MET signaling in fibrosis |
| EGR1 | Early growth response 1 transcription factor | Mediates Ninjurin2 effects on PDGF-BB |
| PDGF-BB | Platelet-derived growth factor BB | Promotes stellate cell activation; linked to MET signaling |
| PAX6 | Transcription factor enhancing MET/STAT5A | Promotes neuroendocrine prostate cancer; opposes negative regulation |
| STAT5A | Signal transducer and activator of transcription 5A | Downstream of MET; chromatin remodeling |
| PDK4 | Pyruvate dehydrogenase kinase 4 | Glucocorticoid receptor target; metabolic reprogramming in breast cancer |
| GR | Glucocorticoid receptor | Drives migration via PDK4; may intersect MET |
| CBLB | Cbl-b E3 ubiquitin ligase | Negative regulator of receptor tyrosine kinases |
| CBLC | Cbl-c E3 ubiquitin ligase | Negative regulator of receptor tyrosine kinases |
| SPRY2 | Sprouty homolog 2 | Feedback inhibitor of RTK signaling |
| SOCS1 | Suppressor of cytokine signaling 1 | May modulate MET downstream signaling |
| PTPN11 | SHP2 phosphatase | Can positively or negatively regulate RTK signaling |
How Is negative regulation of hepatocyte growth factor receptor signaling pathway Regulated?
The negative regulation of HGF receptor signaling is itself controlled by multiple mechanisms. Cbl-family E3 ubiquitin ligases are recruited to activated MET and their activity can be modulated by phosphorylation and adaptor proteins. CXCL13 expression is regulated during liver injury and regeneration, providing a layer of physiological control. Additionally, downstream effectors such as ERK and AKT can initiate negative feedback loops that attenuate MET signaling. In cancer, glucocorticoid receptor signaling via PDK4 may influence metabolic reprogramming that intersects with MET pathways.
negative regulation of hepatocyte growth factor receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| NINJ2 | Liver fibrosis | Knockout mouse or hepatic stellate cell co-culture |
| CXCL13 | Liver regeneration | Overexpression or knockout in hepatocytes |
| CBL | Cancer (sustained MET signaling) | Point mutation of Cbl ubiquitin ligase domain |
| PAX6 | Neuroendocrine prostate cancer | Knockdown or knockout in prostate cancer cell lines |
| MET | Neuroblastoma | Knock-in of activating mutations or overexpression |
Liver fibrosis and hepatocellular carcinoma
Impaired negative regulation of HGF receptor signaling contributes to liver fibrosis and hepatocellular carcinoma. Hepatocyte Ninjurin2 promotes hepatic stellate cell activation and fibrosis through IGF1R/EGR1/PDGF-BB signaling, which can disrupt the balance of HGF/MET signaling. Loss of negative regulators such as Cbl leads to sustained MET activation, promoting tumorigenesis.
Breast cancer
Glucocorticoid receptors drive breast cancer cell migration and metabolic reprogramming via PDK4, a pathway that may intersect with MET signaling. Negative regulation of HGF receptor signaling is important to prevent excessive migration and invasion in breast cancer cells.
Prostate cancer
PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility. This indicates that negative regulation of MET signaling is bypassed in aggressive prostate cancer subtypes.
Neuroblastoma
Hepatocyte growth factor/c-Met signaling promotes the progression of experimental human neuroblastomas. Negative regulation of this pathway is therefore a potential therapeutic strategy to limit neuroblastoma growth.
From negative regulation of hepatocyte growth factor receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of Cbl lead to sustained MET signaling? | CBL knockout cell line |
| Does CXCL13 negatively regulate HGF signaling in vivo? | CXCL13 overexpression or knockout mouse |
| Does Ninjurin2 promote fibrosis via MET cross-talk? | NINJ2 knockout hepatocytes |
| Does PAX6 enhance MET/STAT5A chromatin accessibility? | PAX6 point mutation or knockout in prostate cancer cells |
| Does PDK4 mediate glucocorticoid-driven migration? | PDK4 knockout breast cancer cells |
| Does HGF/c-Met promote neuroblastoma progression? | MET overexpression or knockdown in neuroblastoma cells |
How to Study the negative 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 negative regulators |
| Phosphoproteomics | Phosphorylation changes in MET pathway | Quantify signaling attenuation |
| Ubiquitination assay | MET ubiquitination levels | Confirm E3 ligase function |
| RNA-seq | Transcriptional changes | Assess downstream gene expression |
| ATAC-seq | Chromatin accessibility | Study PAX6/STAT5A-mediated remodeling |
| Co-immunoprecipitation | Protein-protein interactions | Detect Cbl-MET binding |
| Liver regeneration models | Hepatocyte proliferation | Test CXCL13 negative regulation |
| Cell migration assays | Migration capacity | Evaluate breast cancer phenotypes |
CRISPR knockout screens
Genome-wide CRISPR knockout screens can identify negative regulators of HGF receptor signaling by selecting for cells with enhanced MET downstream activity. This approach has been used to uncover Cbl-family E3 ligases as key negative regulators.
Phosphoproteomics
Phosphoproteomic profiling after HGF stimulation can reveal changes in MET phosphorylation and downstream signaling when candidate negative regulators are perturbed [7, 5].
Ubiquitination assays
In vivo and in vitro ubiquitination assays measure MET ubiquitination levels and can confirm the role of E3 ligases such as Cbl in negative regulation.
RNA-seq and chromatin accessibility
RNA-seq and ATAC-seq can assess transcriptional and chromatin changes following manipulation of negative regulators, as shown for PAX6-MET/STAT5A axis in prostate cancer.
How CRISPR Can Be Used to Study GO:1902203 negative regulation of hepatocyte growth factor receptor signaling pathway
Knockout
CRISPR knockout of negative regulators such as CBL or CXCL13 can be used to assess whether their loss enhances HGF/MET signaling and downstream phenotypes like proliferation or migration [7, 5].
Point Mutation
Point mutations in the ubiquitin ligase domain of CBL can abrogate its ability to ubiquitinate MET, providing mechanistic insights into negative regulation.
Knock-in
Knock-in of tagged MET or Cbl alleles allows tracking of receptor ubiquitination and trafficking in live cells, revealing dynamic negative regulation.
Overexpression
Overexpression of CXCL13 or other negative regulators can suppress HGF-driven liver regeneration or tumor growth, validating their inhibitory role.
How EDITGENE Supports negative regulation of hepatocyte growth factor receptor signaling pathway Research
Researchers studying negative regulation of hepatocyte growth factor receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in attenuating MET signaling. EDITGENE provides a comprehensive suite of CRISPR services to enable such functional studies.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of hepatocyte growth factor receptor signaling pathway research.
Frequently Asked Questions About negative regulation of hepatocyte growth factor receptor signaling pathway
What is GO:1902203?
GO:1902203 is the Gene Ontology term for negative regulation of hepatocyte growth factor receptor signaling pathway, describing processes that stop or reduce HGF/MET signaling.
What genes are involved in negative regulation of HGF receptor signaling?
Key genes include CBL, CXCL13, NINJ2, and other modulators of MET trafficking and downstream feedback [7, 5, 1].
How is HGF receptor signaling negatively regulated?
It is negatively regulated by mechanisms such as Cbl-mediated ubiquitination and degradation of MET, feedback inhibition, and chemokine suppression [7, 5].
What diseases are associated with defective negative regulation of MET signaling?
Defective negative regulation is linked to liver fibrosis, hepatocellular carcinoma, breast cancer, prostate cancer, and neuroblastoma [1, 4, 2, 8].
What is the role of Cbl in MET signaling?
Cbl is an E3 ubiquitin ligase that ubiquitinates MET, leading to its degradation and termination of signaling.
How does CXCL13 affect liver regeneration?
CXCL13 suppresses liver regeneration through negative regulation of HGF signaling.
Can CRISPR be used to study negative regulation of HGF receptor signaling?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are powerful tools to dissect this pathway [7, 5].
What experimental models are used to study GO:1902203?
Common models include knockout mice, cell lines with CRISPR edits, and liver regeneration models [5, 7].
What is the connection between PAX6 and MET signaling in prostate cancer?
PAX6 enhances MET/STAT5A-mediated chromatin accessibility, promoting neuroendocrine phenotypes.
How does Ninjurin2 contribute to liver fibrosis?
Hepatocyte Ninjurin2 promotes hepatic stellate cell activation and fibrosis via IGF1R/EGR1/PDGF-BB signaling, indirectly affecting HGF/MET balance.
Conclusion
GO:1902203, negative regulation of hepatocyte growth factor receptor signaling pathway, is a critical biological process that maintains tissue homeostasis and prevents disease. Key negative regulators such as Cbl, CXCL13, and Ninjurin2 modulate MET signaling through ubiquitination, feedback inhibition, and cross-talk with other pathways [7, 5, 1]. Dysregulation of this process contributes to liver fibrosis, cancer, and other pathologies [1, 4, 8]. CRISPR-based models and multi-omics approaches are essential to further dissect these mechanisms and identify therapeutic targets.
References
- 1. Wang Y et al.. 2023. Hepatocyte Ninjurin2 promotes hepatic stellate cell activation and liver fibrosis through the IGF1R/EGR1/PDGF-BB signaling pathway.. Metabolism 140:155380 PMID: 36549436
- 2. Dwyer AR et al.. 2023. Glucocorticoid Receptors Drive Breast Cancer Cell Migration and Metabolic Reprogramming via PDK4.. Endocrinology 164(7) PMID: 37224504
- 3. Bardelli A et al.. 1994. Identification of functional domains in the hepatocyte growth factor and its receptor by molecular engineering.. J Biotechnol 37(2):109-22 PMID: 7765452
- 4. Jing N et al.. 2024. PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility.. J Exp Clin Cancer Res 43(1):144 PMID: 38745318
- 5. Zhao Q et al.. 2025. CXCL13 suppresses liver regeneration through the negative regulation of HGF signaling.. Cell Death Dis 16(1):361 PMID: 40325003
- 7. Tang R et al.. 2022. Negative regulation of receptor tyrosine kinases by ubiquitination: Key roles of the Cbl family of E3 ubiquitin ligases.. Front Endocrinol (Lausanne) 13:971162 PMID: 35966060
- 8. Hecht M et al.. 2004. Hepatocyte growth factor/c-Met signaling promotes the progression of experimental human neuroblastomas.. Cancer Res 64(17):6109-18 PMID: 15342394
