MET
MET is a master receptor tyrosine kinase that serves as the "architect" of tissue invasion and repair. By sensing Hepatocyte Growth Factor (HGF) and triggering programs for cell scattering and survival, it dictates organ development and wound closure; however, its hyperactivation is a hallmark of metastatic cancer and a primary escape route for tumors resisting other targeted therapies.
Key Takeaways
- •MET is the "invasive growth" receptor, telling cells when to detach, migrate, and rebuild tissues.
- •It is the primary "escape hatch" for lung cancers; tumors often amplify MET to bypass other drugs.
- •The Exon 14 Skip is a unique mutation that removes the receptors off-switch, leading to relentless signaling.
- •MET is essential for liver and kidney repair; its decline with age may contribute to slower organ regeneration.
- •Highly selective inhibitors like Capmatinib are now used to target specific MET errors with extreme precision.
Basic Information
- Gene Symbol
- MET
- Full Name
- MET Proto-Oncogene, Receptor Tyrosine Kinase
- Also Known As
- c-MetHGFRAUTS9RCCP2
- Location
- 7q31.2
- Protein Type
- Receptor Tyrosine Kinase
- Protein Family
- MET family
Related Isoforms
The canonical full-length receptor that mediates HGF signaling.
Key SNPs
Kinase domain mutation found in hereditary renal cancer; leads to constitutive activation.
Activation loop mutation that confers resistance to several MET inhibitors.
Kinase domain variant associated with hereditary and sporadic renal cancers.
Polymorphism that may influence MET expression levels and susceptibility to liver disease.
Common variant used in association studies for various cancers and developmental traits.
Overview
MET is a receptor tyrosine kinase that functions as the cellular gateway for Hepatocyte Growth Factor (HGF). In a healthy body, this pathway is the architect of tissue repair and organ development. When HGF binds to MET, it triggers a program known as "invasive growth"—a coordinated series of events where cells divide, break free from their neighbors, and migrate to new areas to heal a wound or form a new blood vessel.
In clinical oncology, MET is famous for two things: its role in metastasis and its role in drug resistance. Because it controls the "scattering" of cells, overactive MET is a primary driver of cancer spreading to other organs. Furthermore, tumors often use MET as a "bypass road"—when a drug blocks another receptor like EGFR, the tumor simply upregulates MET to keep the growth signals flowing, making it a critical target for combination therapy.
Conceptual Model
A simplified mental model for the pathway:
Activating MET mutations (like Exon 14 skip) prolong the Gateway being open, allowing the Program to run uncontrolled.
Core Health Impacts
- • Organogenesis: Essential for embryonic liver and kidney organ development.
- • Wound Healing: Master regulator of epithelial wound healing and repair.
- • Invasive Growth: Drives metastasis in multiple solid tumors through cell scattering.
- • Secondary Resistance: Primary mediator of escape from EGFR-targeted therapies.
- • Neural Development: Influences the migration of muscle precursors and neural cells.
Protein Domains
SEMA Domain
Large N-terminal region responsible for HGF ligand binding.
Juxtamembrane
Contains the CBL binding site; site of Exon 14 skipping mutations.
Kinase Domain
The internal engine that performs tyrosine phosphorylation.
Upstream Regulators
Hepatocyte Growth Factor (HGF) Activator
The only known high-affinity ligand; induces receptor dimerization and robust activation.
Exon 14 Skipping Activator
Mutation that removes the juxtamembrane region responsible for receptor degradation.
Gene Amplification Activator
Massive increase in copy number, common in gastric cancer and as a resistance mechanism.
AXL & EGFR Crosstalk Modulator
MET can heterodimerize with other RTKs, providing bypass signals that promote survival.
Acidic Environment Activator
Low extracellular pH in the tumor microenvironment can enhance HGF-MET interaction.
Proteolytic Activation Activator
HGF must be cleaved by serine proteases to become a fully active ligand for MET.
Downstream Targets
PI3K / AKT Pathway Activates
Critical for protection against apoptosis and for metabolic reprogramming in MET-driven tumors.
MAPK / ERK Pathway Activates
Drives cell proliferation and the invasive growth program downstream of HGF.
STAT3 Activates
Mediates survival signals and contributes to epithelial-mesenchymal transition (EMT).
Src Kinase Activates
Interacts with MET to promote cell motility, invasion, and breakdown of junctions.
Gab1 Activates
A critical scaffolding protein that recruits multiple signaling effectors to the activated receptor.
Rac1 / Rho Activates
Small GTPases that regulate the cytoskeleton, promoting the scattering of epithelial cells.
Role in Aging
MET signaling is a key factor in balancing regenerative capacity with age-related oncogenic risk across various organ systems.
Tissue Regeneration
MET activity is essential for liver and skin repair; its decline may contribute to slower healing in the elderly.
Oncogenic Fitness
Upregulation of MET is a common survival adaptation in tumors as they evolve under the pressure of aging.
SASP Interaction
The Senescence-Associated Secretory Phenotype often includes HGF, which can promote tumor invasiveness.
Stem Cell Support
MET signaling supports the survival of certain stem cell niches; its loss may lead to regenerative exhaustion.
Autophagy Block
Strong activation of the PI3K/mTOR axis downstream of MET can suppress cellular cleanup mechanisms.
Fibrosis Regulation
MET signaling can have anti-fibrotic effects in some organs, potentially mitigating pro-aging scarring.
Disorders & Diseases
Lung Cancer (NSCLC)
MET is a critical driver through Exon 14 skipping mutations or high-level amplification.
Gastric Cancer
A subset of gastric tumors exhibit massive MET amplification, leading to aggressive behavior.
Renal Cell Carcinoma
Hereditary Papillary Renal Cell Carcinoma (HPRCC) is caused by germline mutations in the MET kinase domain.
Hepatocellular Carcinoma
HGF and MET are often overexpressed, contributing to tumor growth and angiogenesis.
Glioblastoma
MET signaling is associated with the highly invasive nature of brain tumor cells.
Interventions
Supplements
Cruciferous-derived compound studied for its potential to modulate MET expression in models.
Polyphenol investigated for its ability to interfere with HGF-mediated signaling and invasion.
Green tea extract reported to inhibit MET phosphorylation and downstream cascades in research.
May support general metabolic health during growth factor targeted treatments.
Lifestyle
Maintaining liver function is important as the liver is the primary source of circulating HGF.
Obesity can elevate systemic growth factor levels that may influence RTK tone.
Improves metabolic health and may modulate the inflammatory environment of growth signaling.
Crucial for lung cancer patients to prevent further genomic damage and RTK mutations.
Medicines
Highly selective MET inhibitor approved for NSCLC with MET exon 14 skipping mutations.
Potent, selective MET inhibitor used for patients with MET exon 14 skipping in lung cancer.
Multi-kinase inhibitor originally used for MET-amplified tumors and ALK+ cancers.
Multi-kinase inhibitor targeting MET, VEGFR2, and AXL; used in renal and thyroid cancers.
Selective MET inhibitor being studied in papillary renal cell carcinoma and gastric cancer.
Lab Tests & Biomarkers
Status Testing
Detection of splice-site mutations; RNA-based testing is more sensitive.
Standard assay to detect gene amplification and differentiate it from polysomy.
Monitoring for acquired MET amplification or resistance mutations in blood.
Monitoring
Mandatory for patients on MET inhibitors due to the risk of hepatotoxicity.
A common and characteristic side effect of targeted MET inhibition.
Measures MET protein levels on the cell surface via immunohistochemistry.
Hormonal Interactions
Estrogen Contextual Modulator
Can influence MET expression and signaling in breast and lung tissues.
Insulin / IGF-1 Growth Synergist
Crosstalk between insulin and MET can amplify oncogenic survival signals.
Growth Hormone Indirect Amplifier
Influences hepatic production of HGF, potentially modulating RTK activity.
Cortisol Stress Regulator
Glucocorticoids can modulate the expression of HGF during tissue repair.
Deep Dive
Network Diagrams
MET Exon 14 Skipping Logic
Bypass Resistance Mechanism
The Exon 14 Skip: How an Off-Switch Disappears
Normally, the MET receptor is a very short-lived signal. After it is activated, a protein called CBL binds to its juxtamembrane domain and marks the receptor for immediate destruction.
- The Structural Glitch: Splicing mutations can cause the cell to accidentally skip “Exon 14” when making the MET protein. This exon happens to be the one that contains the docking site for CBL.
- The Result: The resulting protein is perfectly functional at signaling, but it is “immortal”—it cannot be destroyed. It remains on the cell surface for hours or days, flooding the cell with relentless growth signals. This “Exon 14 Skip” is a defining feature of a highly aggressive subset of lung cancers.
MET as the “Bypass Master” of Resistance
One of the most important concepts in modern precision oncology is the idea of Bypass Resistance, and MET is its primary practitioner.
- The EGFR Escape: In lung cancer, when a patient is treated with an EGFR inhibitor like Osimertinib, the tumor eventually stops responding. In up to 20% of these cases, the reason is that the tumor has made thousands of extra copies of the MET gene (amplification).
- The Workaround: These extra MET receptors can activate the exact same downstream survival “pipes” (PI3K and MAPK) as the blocked EGFR. The tumor has essentially built a bypass road around the drug blockade. This has led to successful new treatments that combine both EGFR and MET inhibitors to shut off all exits for the tumor.
Invasive Growth: From Repair to Metastasis
The MET pathways natural job is to promote Invasive Growth. During wound healing, this allows epithelial cells to lose their “anchors,” crawl across a gap, and multiply to seal the wound.
Cancer hijacks this program to drive Metastasis. When MET is hyperactivated, the tumor cells undergo an “Epithelial-to-Mesenchymal Transition” (EMT). They become mobile, invasive, and able to survive in the bloodstream. By understanding MET, scientists are learning how to turn off the “engines of invasion” that allow a local tumor to become a systemic disease.
Interpreting MET Status
Amplification vs Polysomy. In FISH tests, true gene amplification predicts drug response, while polysomy (extra chromosomes) usually does not.
Acquired Alterations. MET fusions and amplifications often appear AFTER a patient has been treated with other drugs like Osimertinib.
Relevant Research Papers
Links go to PubMed (abstracts are public); some papers also offer free full text via PMC or the publisher.
Discovered HGF (scatter factor) as a potent regulator of epithelial cell motility.
The landmark study identifying MET as the functional receptor for HGF.
Defined MET exon 14 skipping as a clinically actionable target in NSCLC.
Discovered MET amplification as a major mechanism of bypass resistance to EGFR inhibitors.
Clinical trial (VISION) establishing the efficacy of selective MET inhibition.
Comprehensive review of the MET pathway in normal repair and oncogenic progression.