Hepatocyte growth factor receptor

The hepatocyte growth factor receptor (HGFR), commonly known as c-MET or MET, is a single-pass transmembrane receptor tyrosine kinase encoded by the MET proto-oncogene located on chromosome 7q31, which specifically binds the ligand hepatocyte growth factor (HGF)—also termed scatter factor—to initiate signaling cascades that control epithelial cell proliferation, survival, motility, and morphogenesis during development and tissue repair.^[1]^[2] Structurally, c-MET is synthesized as a 150 kDa precursor polypeptide that undergoes glycosylation to 170 kDa and proteolytic cleavage into disulfide-linked α (50 kDa) and β (140 kDa) chains, forming a heterodimer with an extracellular domain comprising a semaphorin (SEMA) region for ligand binding, a plexin-semaphorin-integrin (PSI) module, four immunoglobulin-like plexin-transcription factor (IPT) domains, a single transmembrane helix, and an intracellular portion including a juxtamembrane region and a tyrosine kinase (TK) domain.^[1]^[3] HGF, its sole ligand, is produced as an inactive 90 kDa single-chain precursor by mesenchymal cells and activated through proteolytic processing into a bioactive heterodimer consisting of an α-chain (with an N-terminal hairpin and four kringle domains) and a serine protease-like β-chain, enabling paracrine signaling.^[2] Upon HGF binding, c-MET undergoes dimerization, leading to autophosphorylation of key tyrosine residues (Y1234/Y1235 in the activation loop and Y1349/Y1356 in the C-terminal tail), which recruits adaptor proteins like Grb2, Gab1, PI3K, and STAT3 to activate downstream pathways including MAPK/ERK (for proliferation), PI3K/AKT (for survival), and FAK/Src (for motility).^[1]^[3]^[2] In normal physiology, c-MET signaling is indispensable for embryonic development—such as myogenesis, liver and placenta formation—and adult tissue regeneration, particularly in the liver following injury, where it promotes hepatocyte proliferation and inhibits apoptosis to facilitate repair.^[1]^[2] Dysregulation of c-MET, through mechanisms like gene amplification, overexpression, or activating mutations (e.g., in the TK domain for papillary renal carcinoma or juxtamembrane for lung cancer), transforms it into an oncogene that drives tumor invasion, metastasis, and resistance to therapy in various malignancies, including gastric, lung, and hepatocellular carcinomas, making it a prominent therapeutic target for inhibitors such as tyrosine kinase inhibitors (e.g., cabozantinib) and monoclonal antibodies. As of 2025, additional MET-targeted therapies, including combinations of tyrosine kinase inhibitors with EGFR inhibitors, have been approved for specific cancers such as non-small cell lung cancer.^[1]^[2]^[4]

Genetics

Gene Structure

The MET proto-oncogene, encoding the hepatocyte growth factor receptor (also known as c-MET), is located on the long arm of human chromosome 7 at the 7q31.2 locus. It spans approximately 125 kb of genomic DNA and consists of 21 exons interrupted by 20 introns, with exon sizes ranging from 81 bp (exon 16) to 2.5 kb (exon 21). All exons are flanked by canonical GT-AG dinucleotide splice sites at the 5' and 3' boundaries, respectively. Exon 1 is entirely non-coding and contains most of the 5' untranslated region (UTR), while exon 2 is the largest internal coding exon at 1214 nucleotides and includes the ATG start codon for the receptor protein.^[5]^[6]^[7] The genomic organization of MET reflects its functional domains, with exons 2 through 13 encoding the extracellular and transmembrane regions, and exons 14 through 21 specifying the intracellular tyrosine kinase domain, which spans about 30 kb of genomic sequence. Exon 21, the largest, encodes the carboxy-terminal tail and a long 3' UTR. Specific nucleotide motifs within the kinase domain-encoding exons include conserved sequences critical for ATP binding and phosphotransfer, such as the glycine-rich loop in exon 15 and the activation loop in exon 19.^[7]^[8] Alternative splicing of the MET pre-mRNA generates multiple isoforms, including the full-length transcript (isoform a, NM_001127500.3) and shorter variants such as isoform b (NM_000245.4), which lacks part of the beta chain, and isoform c (NM_001324401.3), a truncated form missing the intracellular domain. Notable splicing events include frequent skipping of exon 2, producing a ubiquitous 7 kb transcript with no detectable protein product, and exclusion of exon 13, yielding a Δ13MET isoform predominantly expressed in human liver that alters ligand binding. These isoforms arise from exon-intron boundary recognition by splicing factors, with no evidence of complex alternative promoter usage in the wild-type gene.^[5]^[7]^[9] The MET gene exhibits strong evolutionary conservation across mammalian species, with orthologs identified in rodents, primates, and other mammals showing over 85% nucleotide sequence identity in the coding regions, particularly in the kinase domain exons. This homology underscores the essential role of MET in developmental and regenerative processes, as evidenced by functional conservation in mouse and rat models.^[5]^[10]

Mutations and Variants

The MET gene, encoding the hepatocyte growth factor receptor (also known as c-MET), harbors various germline and somatic mutations that drive oncogenesis across multiple cancer types. Germline variants are primarily associated with hereditary papillary renal cell carcinoma (HPRC), an autosomal dominant disorder characterized by multifocal and bilateral type 1 papillary renal tumors. These variants consist of missense mutations clustered in the tyrosine kinase domain, such as M1149T, V1206L, V1238I, D1246N, and Y1248C, which flank the activation loop tyrosines Y1234 and Y1235. These mutations result in constitutive activation of the MET receptor, promoting uncontrolled cell proliferation and tumor formation even in the heterozygous state.^[11]^[12] Somatic mutations in MET occur in both the juxtamembrane and tyrosine kinase domains, contributing to tumorigenesis in sporadic cancers. In the kinase domain, activating missense mutations like Y1230C and D1246N enhance receptor kinase activity by mimicking autophosphorylation at key tyrosines, leading to ligand-independent signaling and increased cell motility and invasion. The Y1230C mutation has been identified in carcinoma metastases, while D1246N appears in colorectal cancers and confers resistance to MET inhibitors in non-small cell lung cancer (NSCLC). Overall somatic MET mutation prevalence is approximately 5.6% in NSCLC and up to 8% in lung adenocarcinomas, with lower rates in other solid tumors such as 3% in squamous cell lung cancers and 7-9% in advanced breast or ovarian cancers.^[12]^[13] A prominent activating alteration is MET exon 14 skipping (MET∆14), which results from mutations or deletions in splice sites flanking exon 14, leading to loss of a juxtamembrane tyrosine (Y1003) critical for receptor ubiquitination and degradation. This impairs c-Cbl-mediated downregulation, causing MET protein accumulation, enhanced stability, and constitutive signaling that promotes tumor cell survival and metastasis. MET∆14 occurs in 2-4% of NSCLC cases, with a median frequency of 2.0% across unselected patients and higher rates (up to 12%) in sarcomatoid histology; it is rare in other drivers like EGFR mutations.^[14]^[15]^[12] Gene amplification represents another key oncogenic variant, involving increased MET copy numbers that drive overexpression and hypersensitivity to hepatocyte growth factor. In NSCLC, MET amplification is detected in 3-5% of cases, particularly among patients with acquired resistance to EGFR tyrosine kinase inhibitors (up to 20% of such cases), and correlates with aggressive disease progression through sustained downstream pathway activation.^[12] Polymorphisms in MET, such as single nucleotide variants in non-coding regions, have been linked to modest risks for certain cancers but lack the strong oncogenic potential of the above alterations. These genetic changes collectively underscore MET's role as a therapeutic target, with downstream effects including hyperactivation of PI3K/AKT and MAPK pathways that fuel tumor growth.^[12]

Protein Structure

Extracellular Domain

The extracellular domain of the hepatocyte growth factor receptor (MET), also known as c-MET, consists of a disulfide-linked α-β heterodimer derived from proteolytic processing of a single-chain precursor. This cleavage occurs between Arg307 and Ser308, yielding an α-chain of approximately 32 kDa (residues 25–307 of the mature protein) and a β-chain of about 120 kDa (residues 308–932). The α-chain encompasses the N-terminal portion of the Sema domain, while the β-chain includes the C-terminal Sema region, the PSI domain, and four immunoglobulin-like plexin-transcription factor (IPT) domains; at least three interchain disulfide bonds, such as Cys282-Cys409 and Cys298-Cys363, covalently link the chains to maintain structural integrity.^[3]^[16] The Sema domain, spanning residues 25–515, forms a seven-bladed β-propeller fold characteristic of semaphorin family members and serves as the primary site for hepatocyte growth factor (HGF) binding. This domain adopts a compact structure stabilized by seven intrachain disulfide bonds, with the bottom face of blades 2 and 3 directly interacting with the serine protease-like β-chain of HGF to initiate ligand recognition. Key residues within the Sema domain, including His296 and Tyr295, contribute to this high-affinity interaction by forming hydrogen bonds and hydrophobic contacts with HGF, as revealed in crystallographic studies.^[16]^[3]^[17] Adjacent to the Sema domain, the PSI (plexin-semaphorin-integrin) domain (residues 516–562) comprises approximately 50 amino acids rich in cysteine residues, forming four disulfide bonds that rigidify the linker region between the Sema and IPT domains. This domain plays a crucial role in stabilizing the overall extracellular architecture, facilitating proper orientation for ligand-induced dimerization without directly participating in HGF binding; flexibility at the Sema-PSI junction, conferred by Gly517 and Gly519, allows conformational adjustments during activation.^[17]^[18] The four C-terminal IPT domains (IPT1–4, spanning roughly residues 563–932) exhibit immunoglobulin-like folds akin to plexin-WD motifs and mediate receptor dimerization essential for signaling initiation. Specifically, IPT3 and IPT4 provide a high-affinity binding site for the HGF α-chain, complementing the low-affinity Sema interaction to promote full heterodimerization of MET receptors upon HGF engagement.^[19]^[17] The extracellular domain features multiple N-linked glycosylation sites, primarily in the Sema and IPT regions, which support proper protein folding and trafficking but do not significantly alter HGF binding affinity when removed in vitro. These glycans, numbering up to nine in the full extracellular portion, enhance structural stability and may modulate ligand accessibility indirectly through conformational effects. Crystal structures, such as the HGF β-chain complex with the Sema-PSI domains (PDB: 1SHY), illustrate these features at 2.6 Å resolution, highlighting the disulfide-rich topology and binding interface.^[20]^[21]^[16]

Transmembrane and Intracellular Domains

The hepatocyte growth factor receptor, known as MET, features a single transmembrane helix spanning residues 933–955, which anchors the receptor in the plasma membrane and promotes dimerization in response to ligand binding through motifs such as GxxxG that mediate helix-helix interactions.^[18] This hydrophobic alpha-helical segment, approximately 23 amino acids long, transmits conformational changes from the extracellular domain to the intracellular region upon hepatocyte growth factor (HGF) engagement, facilitating receptor activation without direct enzymatic function.^[2] Adjacent to the transmembrane helix lies the intracellular juxtamembrane domain, encompassing residues 956–1077, which serves as a regulatory hub containing key tyrosine residues like Y1003.^[2] Phosphorylation of Y1003 recruits the E3 ubiquitin ligase CBL, triggering ubiquitination of MET and directing the receptor toward lysosomal degradation to attenuate signaling and prevent prolonged activation.^[2] This domain's length and composition, including a conserved DpYR motif, also contribute to inhibitory interactions that fine-tune kinase activity prior to full receptor stimulation.^[22] The core of MET's intracellular signaling resides in the tyrosine kinase domain, spanning residues 1078–1343, a catalytic region responsible for phosphorylating downstream substrates upon activation.^[23] Within the activation loop of this domain, tyrosines Y1234 and Y1235 undergo autophosphorylation, which stabilizes an open conformation of the kinase and enhances catalytic efficiency, representing a critical step in transducing HGF-induced signals.^[22] Mutations or dysregulation in this domain can lead to constitutive activity, underscoring its role in both physiological and pathological contexts.^[23] The C-terminal tail, comprising residues 1344–1390, extends beyond the kinase domain and harbors multifunctional docking sites that recruit adaptor proteins to propagate signals.^[2] Phosphorylation of specific motifs, such as Y1349 and Y1356, creates binding platforms for effectors like the p85 subunit of PI3K at Y1349 and GRB2 at Y1356, enabling diverse downstream cascades while the tail's autoinhibitory interactions are relieved during activation.^[2] This short regulatory segment ensures signal specificity and termination through its integration with degradation pathways.^[2]

Expression and Regulation

Tissue Distribution

The hepatocyte growth factor receptor, encoded by the MET gene, exhibits high expression primarily in epithelial cells of several key organs, including the liver, kidney, lung, and placenta. According to GTEx RNA-seq data, MET shows elevated transcript levels in these tissues, with the liver displaying among the highest median TPM values across adult human samples, followed closely by kidney and lung epithelia.^[24] In the placenta, MET is prominently expressed in trophoblast cells, supporting roles in placental development and function, as demonstrated by RT-PCR and in situ hybridization studies showing robust mRNA presence in villous trophoblasts.^[25] During development, MET expression peaks prominently during embryogenesis, particularly in branching organs such as the lungs and kidneys, where it facilitates epithelial morphogenesis and ureteric bud branching. In mouse embryos, in situ hybridization reveals strong MET transcripts in epithelial cells of the developing lung, kidney, and liver from embryonic day 11 onward, correlating with critical phases of organogenesis. This pattern underscores MET's conserved role in epithelial proliferation and migration during fetal tissue formation. In adults, MET maintains expression in stem cell niches, such as mesenchymal stem cells in bone marrow and muscle satellite cells, and is upregulated during wound healing processes in skin and other tissues to promote repair and regeneration. The full-length isoform predominates in epithelial contexts, enabling full signaling capacity, whereas truncated isoforms appear more restricted in non-epithelial cells.^[26]^[27] Expression patterns of MET are highly conserved across species, with mouse models recapitulating human tissue distribution; for instance, GTEx-equivalent analyses in mice show elevated MET in liver, kidney, and lung epithelia, as well as similar developmental upregulation in branching organs.^[28]

Transcriptional and Post-transcriptional Control

The MET gene promoter features specific elements that facilitate binding by key transcription factors to regulate its expression. SP1 binds to GC-rich motifs within the promoter to drive basal transcription, while ETS family transcription factors recognize Ets-binding sites to enhance MET expression in various cellular contexts. E-box motifs (CANNTG sequences) in the promoter are targeted by basic helix-loop-helix transcription factors, such as MITF, which upregulate MET in melanocytes and related lineages. In cancer, hypoxic environments activate the hypoxia-inducible factor (HIF-1), which binds to multiple hypoxia response elements (HREs) in the MET promoter, inducing transcriptional activation and supporting tumor invasion and metastasis.^[29]^[2]^[30]^[31] Epigenetic mechanisms, particularly histone modifications, provide an additional layer of transcriptional control over MET. Acetylation of histones at the MET promoter, mediated by histone acetyltransferases, correlates with euchromatin formation and elevated gene expression during embryonic development and in aggressive cancers, where it facilitates MET overexpression. This modification contrasts with repressive marks like DNA hypermethylation, which can silence the locus in normal tissues.^[29] Post-transcriptional regulation fine-tunes MET mRNA levels and processing. The miR-34 family of microRNAs, transcriptionally activated by p53, directly targets conserved sites in the 3' untranslated region (3'UTR) of MET mRNA, promoting its degradation and translational inhibition to maintain low MET levels in non-transformed cells. Dysregulation of miR-34 in cancers relieves this suppression, contributing to MET accumulation. Alternative splicing of the MET pre-mRNA results in inclusion of exon 14, encoding the juxtamembrane domain critical for receptor ubiquitination and turnover; variants with exon 14 inclusion predominate in normal physiology, while skipping generates stable oncogenic isoforms.^[32]^[33]^[34]

Signaling Pathways

Activation Mechanism

The activation of the hepatocyte growth factor receptor (MET) is initiated by the binding of its ligand, hepatocyte growth factor (HGF), which is secreted as an inactive single-chain precursor known as pro-HGF. Pro-HGF requires proteolytic processing to its mature two-chain form (α-chain and β-chain linked by a disulfide bond) to enable high-affinity binding to MET. This cleavage is primarily mediated by hepatocyte growth factor activator (HGFA), a serine protease that recognizes and cleaves the Arg-Val bond in pro-HGF, converting it into bioactive HGF; other proteases such as matriptase and hepsin can contribute under specific conditions, but HGFA is the dominant activator in physiological contexts.^[35]^[36] Mature HGF binds to the extracellular domain of MET, which consists of an α-chain (primarily the Sema and PSI domains) and a β-chain (including the Ig-like domains), linked by disulfide bonds following proteolytic maturation of pro-MET. The HGF α-chain engages the high-affinity site on the MET Sema domain, while the HGF β-chain, resembling a serine protease domain, interacts with the low-affinity site spanning the Sema and PSI domains, inducing a conformational rearrangement that promotes MET dimerization. This ligand-induced dimerization assembles a 2:2 HGF-MET complex, where one HGF molecule bridges two MET receptors, bringing the intracellular kinase domains into proximity for trans-autophosphorylation. Cryo-electron microscopy structures reveal that this binding stabilizes an asymmetric dimer interface, facilitating the necessary orientation for kinase activation without direct contact between the kinase domains in the extracellular assembly.^[3]^[18] Upon dimerization, the MET kinase domains undergo activation through autophosphorylation of tandem tyrosine residues Y1234 and Y1235 within the activation loop of the catalytic core, which repositions the loop to open the active site and enhance ATP binding and phosphotransfer efficiency. This initial phosphorylation event further enables sequential autophosphorylation of tyrosines Y1349 and Y1356 in the C-terminal tail, generating multimolecular docking sites for downstream adaptor proteins. Structural analyses indicate that these conformational changes in the kinase domain, including activation loop reorientation, are directly coupled to the extracellular dimerization signal, ensuring rapid signal initiation upon HGF engagement. Computational modeling supports that HGF binding stabilizes these intracellular shifts, with the activation loop adopting an active DFG-in conformation essential for catalysis.^[3]^[18]^[37]

Downstream Signaling Cascades

Upon ligand-induced autophosphorylation, the hepatocyte growth factor receptor (MET) activates multiple downstream signaling cascades through its C-terminal docking sites, primarily involving the phosphotyrosines Y1349 and Y1356. These sites recruit adaptor proteins that initiate pathways promoting cell survival, proliferation, and motility.^[2] The PI3K/AKT pathway is activated when the adaptor protein GAB1 binds to phosphorylated Y1349 on MET, either directly or indirectly via GRB2, recruiting the p85 regulatory subunit of PI3K. This leads to PI3K activation, PIP3 production, and subsequent phosphorylation of AKT, which inhibits pro-apoptotic proteins like BAD and FOXO, thereby enhancing cell survival. Recent studies, including those on MET exon 14 skipping variants, underscore AKT's pivotal role in driving ligand-dependent invasive growth, a process involving epithelial-mesenchymal transition and sustained motility in cancers such as non-small cell lung cancer.^[38] The MAPK/ERK pathway is initiated by the binding of the GRB2-SOS complex to phosphorylated Y1356 on MET, which activates the guanine nucleotide exchange factor SOS to stimulate RAS. This triggers the sequential activation of RAF, MEK, and ERK kinases, culminating in ERK nuclear translocation and induction of genes that drive cell proliferation and migration.^[39]^[40] STAT3 is directly phosphorylated by MET at tyrosine 705 following receptor activation, independent of the canonical JAK pathway, leading to STAT3 dimerization, nuclear translocation, and transcription of anti-apoptotic genes such as BCL2 and MCL1. This direct interaction contributes to MET-mediated protection against apoptosis and invasive phenotypes in tumor cells.^[41] MET signaling exhibits crosstalk with other receptor tyrosine kinases, notably EGFR, where EGFR activation can transphosphorylate MET, amplifying shared downstream effectors like PI3K/AKT and MAPK/ERK to enhance oncogenic signaling in cancers such as breast and lung tumors. Additionally, HGF stimulation induces upregulation of SOCS1, which acts as a negative feedback regulator by promoting MET ubiquitination and proteasomal degradation, thereby attenuating sustained signaling.^[42]^[43]

Physiological Functions

Role in Development

The hepatocyte growth factor receptor (MET) plays an essential role in embryonic placentation by mediating interactions between allantoic mesenchyme and trophoblastic epithelium, which are critical for placental organogenesis. In MET knockout mice, homozygous mutants exhibit embryonic lethality between embryonic days 13.5 and 16.5, primarily due to severe placental defects characterized by a marked reduction in labyrinthine trophoblast cells and impaired vascularization, leading to insufficient nutrient and gas exchange for the fetus.^[44] Additionally, these mutants display hypoplastic liver development, with the embryonic liver being significantly smaller and showing disorganized hepatocyte organization.^[45] MET is pivotal in branching tubulogenesis during the formation of epithelial organs such as the kidney and lung. In kidney development, HGF binding to MET on ureteric bud epithelial cells induces invasive growth and iterative branching, which is fundamental for metanephric mesenchyme induction and subsequent nephron formation; conditional MET inactivation in the ureteric bud lineage results in reduced branching and fewer nephrons.^[46] Similarly, in the lung, HGF/MET signaling promotes mesenchymal-derived morphogenetic cues that drive epithelial budding and elongation, ensuring proper alveolar and bronchial structure; disruption of this pathway impairs fetal lung branching morphogenesis.^[47] MET facilitates neural crest cell migration and myogenesis through targeted expression in somites and migratory populations. During myogenesis, MET is expressed in condensing somites, where HGF/MET signaling regulates the delamination, migration, and proliferation of myogenic precursor cells from the somites into limb buds, diaphragm, and tongue musculature; MET null mutants fail to populate limb muscles, leading to their absence.^[48] For neural crest-derived lineages, HGF/MET promotes the directed migration of melanocyte precursors from the neural crest to the skin and other sites, with targeted disruption causing pigmentation defects due to failed colonization.^[49] These functions of MET are conserved in human embryonic development, with comparable expression patterns in fetal tissues driving organogenesis.^[50]

Role in Tissue Repair and Homeostasis

The hepatocyte growth factor receptor (MET), upon binding its ligand hepatocyte growth factor (HGF), plays a pivotal role in orchestrating tissue repair processes in adult organs by promoting cell proliferation, migration, and survival. In liver regeneration following partial hepatectomy, MET activation drives hepatocyte proliferation essential for restoring liver mass. HGF levels in plasma rise dramatically after injury, increasing approximately 10-fold within hours, which correlates with the initiation of regenerative signaling through MET to stimulate DNA synthesis and cell division in hepatocytes.^[51] This process is critical for compensatory growth, as evidenced by studies showing impaired regeneration in MET-deficient models post-hepatectomy.^[52] In the kidney, MET contributes to repair after acute injury by enhancing the recovery of tubular epithelial cells. Activation of MET by HGF provides anti-apoptotic protection, reducing cell death in proximal tubules exposed to ischemic or toxic insults and facilitating epithelial regeneration through pathways that inhibit caspase activation and promote cell survival.^[53] This renoprotective mechanism is particularly evident in models of acute kidney injury, where MET induction in tubular epithelium correlates with improved functional recovery and reduced fibrosis.^[54] MET also supports cardiac remodeling after myocardial infarction by fostering angiogenesis and tissue repair. HGF/MET signaling promotes endothelial cell proliferation and vessel formation in the infarct border zone, aiding in the restoration of blood supply and limiting adverse ventricular remodeling. Recent studies from 2023 highlight how enhancing HGF/MET activity improves cardiac function post-infarction by reducing cardiomyocyte apoptosis and supporting neovascularization.^[55] Beyond these organs, MET maintains epithelial integrity in the gastrointestinal tract and skin, where it regulates barrier function and wound closure. In the GI mucosa, HGF/MET signaling preserves epithelial homeostasis by promoting cell migration and adhesion, countering injury-induced disruption. In skin, MET is essential for reepithelialization during acute wound healing, but its dysregulated expression—often spatially heterogeneous with upregulation at edges and downregulation in wound beds—contributes to impaired closure in chronic wounds.^[56]^[57]

Pathological Roles

In Cancer

The hepatocyte growth factor receptor (MET) plays a pivotal oncogenic role in various cancers through genetic alterations such as amplification and mutation, which lead to constitutive activation and drive primary tumor formation. In gastric cancer, MET gene amplification occurs in approximately 4-10% of cases, promoting uncontrolled cell proliferation and survival via downstream pathways like PI3K-Akt and MAPK.^[58] MET mutations are rare in gastric cancer but contribute to oncogenesis when present by enhancing tyrosine kinase activity. In papillary renal cell carcinoma (pRCC), somatic MET mutations are found in 13-15% of nonhereditary cases, often in the tyrosine kinase domain, activating the MET pathway and initiating tumorigenesis, while germline mutations underlie hereditary type 1 pRCC.^[59] MET activation significantly contributes to cancer progression by enhancing tumor invasion, metastasis, and angiogenesis. The HGF/MET axis promotes epithelial-mesenchymal transition (EMT), enabling cancer cells to acquire migratory and invasive properties through signaling cascades involving ERK/Akt, Src, and FAK, as observed in cancers such as prostate, colorectal, and hepatocellular carcinoma. This pathway also upregulates vascular endothelial growth factor (VEGF), fostering neovascularization essential for metastatic dissemination in primary and secondary tumors. Aberrant HGF/MET signaling is implicated in 20-30% of advanced solid tumors, where stromal-derived HGF from cancer-associated fibroblasts amplifies these processes.^[60] In therapeutic resistance, MET serves as a bypass mechanism, particularly in non-small cell lung cancer (NSCLC). MET amplification, occurring in 5-20% of EGFR inhibitor-resistant cases, activates ErbB3 and downstream PI3K/Akt signaling independently of EGFR, circumventing targeted therapy. Recent 2025 data further highlight MET's role in immune checkpoint inhibitor (ICI) resistance in advanced NSCLC, where elevated plasma HGF levels correlate with disease progression (p=0.0092) by inhibiting CD8+ T-cell proliferation despite pembrolizumab; HGF/MET inhibitors like crizotinib restore lymphocyte activation and IFNγ production, suggesting potential to overcome this barrier.^[61]^[62] High MET expression holds prognostic significance, notably in hepatocellular carcinoma (HCC), where it correlates with aggressive disease and poor outcomes. Patients with high c-MET protein expression exhibit significantly reduced 5-year survival rates (33.5%) compared to those with low expression (80.3%). In a phase II trial subset, MET-high HCC patients treated with tivantinib showed improved overall survival (7.2 months vs. 3.8 months placebo; HR=0.38, p=0.01), underscoring MET's impact on tumor aggressiveness.^[63]

In Other Diseases

The hepatocyte growth factor receptor (MET) has been implicated in several non-oncological disorders through genetic variants and dysregulated signaling. In autism spectrum disorder (ASD), promoter variants in the MET gene, particularly rs1858830, reduce MET expression in cortical interneurons, disrupting social brain circuitry and increasing ASD susceptibility.^[64] Initial genetic association studies from 2006 identified this variant's role in ASD risk across Caucasian and Han Chinese populations, with subsequent functional analyses up to 2023 confirming its impact on interneuron development and synaptic plasticity.^[65]^[66] In cardiovascular conditions, MET dysregulation contributes to heart failure progression, particularly post-myocardial infarction. Elevated hepatocyte growth factor (HGF) levels correlate with severe heart failure and adverse prognosis, but HGF/MET activation promotes cardioprotection by enhancing angiogenesis, reducing apoptosis, and improving ventricular remodeling after infarction.^[67]^[68] MET plays a protective role in renal diseases such as diabetic nephropathy. Elevated HGF protects podocytes by maintaining nephrin and WT1 expression, reducing apoptosis and oxidative stress via PI3K/Akt-mediated autophagy restoration, and inhibiting fibrosis through suppression of TGF-β signaling and epithelial-mesenchymal transition.^[69]^[70] Emerging research links the HGF/MET axis to chronic liver disease and chronic lymphocytic leukemia (CLL) survival. In non-malignant chronic liver conditions, HGF/MET signaling promotes hepatocyte regeneration and attenuates fibrosis, aiding recovery from inflammation and injury.^[71] In CLL, the axis enhances leukemic cell survival by regulating anti-apoptotic pathways and microenvironment interactions, as demonstrated in a 2025 study identifying it as a potential non-oncological therapeutic target.^[72]

Molecular Interactions

With Tumor Suppressor Genes

The hepatocyte growth factor receptor (MET) interacts with tumor suppressor genes such as PTEN and VHL, modulating oncogenic signaling in specific cancers. In gliomas, loss of PTEN, a lipid and protein phosphatase, amplifies MET-driven activation of the PI3K/AKT pathway, promoting enhanced cell survival and proliferation. PTEN normally antagonizes PI3K signaling by dephosphorylating phosphatidylinositol (3,4,5)-trisphosphate (PIP3), thereby preventing AKT recruitment and activation; however, in PTEN-deficient glioma cells, MET stimulation leads to hyperactivation of AKT, rendering cells hypersensitive to MET inhibition, which reduces AKT phosphorylation by approximately 30% and inhibits cell growth by 80-85%. Reconstitution of PTEN in these models suppresses AKT activity by over 80% and cell growth by 70-75%, underscoring the crosstalk where PTEN loss exacerbates MET-mediated survival signals.^[73] In renal cell carcinoma (RCC), inactivation of the VHL tumor suppressor stabilizes hypoxia-inducible factor-1α (HIF-1α) by preventing its ubiquitination and degradation, leading to transcriptional upregulation of MET expression. This results in constitutive MET phosphorylation independent of its ligand HGF, even under normoxic conditions, driving uncontrolled cell growth and invasion in clear cell RCC. VHL reintroduction suppresses this MET hyperactivation, particularly at high cell densities where intercellular adhesion influences signaling. PTEN further antagonizes MET signaling by directly dephosphorylating AKT at key sites (T308 and S473), counteracting MET-induced AKT activation via its protein phosphatase activity. In clear cell RCC, PTEN loss occurs in approximately 16-20% of cases, potentiating PI3K/AKT hyperactivation and tumor progression.^[74]^[75]^[76] Experimental evidence from genetic mouse models demonstrates that combined MET overexpression and PTEN loss accelerates tumorigenesis. In hydrodynamic injection models of hepatocytes, PTEN knockout synergizes with c-MET overexpression to induce hepatocellular carcinomas as early as 9 weeks post-injection, with all mice developing multifocal tumors by 11-15 weeks, characterized by activated AKT/mTOR and Ras/MAPK pathways, increased proliferation (Ki67-positive), and metabolic reprogramming toward glycolysis and lipogenesis. This cooperative effect depends on intact mTORC2 signaling, as Rictor deletion (a mTORC2 component) abolishes tumor formation, highlighting how suppressor loss amplifies MET-driven oncogenesis.^[77]

With Other Proteins

The hepatocyte growth factor receptor (MET) engages in protein-protein interactions that modulate its localization, activation, and downstream effects, particularly through associations with integrins, caveolin-1, co-receptors like CD44, and regulatory ligases such as CBL. These interactions facilitate MET's role in cellular motility and trafficking without directly invoking tumor suppressor dynamics. MET binds to the α6β4 integrin, forming a complex that enhances cell motility and invasion in response to hepatocyte growth factor (HGF). This association positions α6β4 as a signaling adapter, where the integrin's cytoplasmic domain recruits intracellular effectors to amplify MET-mediated invasive growth in carcinoma cells. For instance, in epithelial cells, HGF stimulation promotes the recruitment of α6β4 to MET, thereby integrating extracellular matrix cues with receptor tyrosine kinase signaling to drive directional migration.^[78]^[79] MET interacts with caveolin-1 (CAV1), a principal component of caveolae, influencing receptor trafficking and localization within lipid rafts. Upon HGF stimulation, this interaction strengthens, leading to CAV1 phosphorylation and co-localization with MET at the plasma membrane, which modulates receptor internalization and sustains invasive signaling in hepatocellular carcinoma cells. CAV1 thereby acts as a scaffold that fine-tunes MET's endocytic routing, potentially altering its availability for ligand binding and promoting prolonged cellular responses.^[80] MET functions with co-receptors such as CD44v6 and RON to amplify HGF responsiveness. CD44v6 serves as a co-receptor by facilitating MET dimerization and activation; it binds HGF and recruits cytoskeletal adaptors like ERM proteins, enabling efficient signal propagation in epithelial and carcinoma cells. Similarly, RON, a related receptor tyrosine kinase, engages in crosstalk with MET through co-expression and shared signaling motifs, enhancing collective responses to ligands like HGF and macrophage-stimulating protein in tumor microenvironments.^[81]^[82]^[83]^[84] Negative regulation of MET occurs via ubiquitination mediated by the E3 ubiquitin ligase CBL, which targets tyrosine 1003 (Y1003) in the receptor's juxtamembrane domain. Phosphorylation of Y1003 recruits CBL, leading to polyubiquitination of MET and its subsequent endocytosis through clathrin-coated pits or caveolae-dependent pathways. This process directs MET to lysosomes for degradation, thereby attenuating prolonged signaling and maintaining homeostasis; mutations at Y1003 impair this ubiquitination, resulting in delayed receptor turnover.^[85]^[86]^[87]

Therapeutic Targeting

MET Kinase Inhibitors

MET kinase inhibitors are small-molecule drugs that target the intracellular kinase domain of the MET receptor tyrosine kinase, blocking its phosphorylation and downstream signaling activation. These inhibitors are primarily ATP-competitive and have been developed to treat MET-driven cancers, particularly non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations. Approved agents demonstrate high potency and selectivity, with clinical trials showing meaningful response rates in targeted patient populations.^[88]^[89] Capmatinib (Tabrecta), a selective type Ib ATP-competitive inhibitor, binds to the active (DFG-in) conformation of the MET kinase domain, forming hydrogen bonds within the ATP-binding pocket to inhibit autophosphorylation. It exhibits an IC50 of 0.13 nM against wild-type MET and demonstrates over 10,000-fold selectivity compared to other receptor tyrosine kinases (RTKs) such as EGFR, VEGFR2, and RON. The U.S. Food and Drug Administration (FDA) granted accelerated approval to capmatinib in May 2020 for adult patients with metastatic NSCLC whose tumors have MET exon 14 skipping mutations, as detected by an FDA-approved test; regular approval followed in August 2022 based on confirmatory data. In the phase II GEOMETRY mono-1 trial, capmatinib achieved an objective response rate (ORR) of 68% (95% CI: 48-84) in treatment-naïve patients with MET exon 14 skipping NSCLC, with a median duration of response of 9.7 months and median progression-free survival of 12.6 months. Updated analyses from 2021 confirmed sustained efficacy, with an ORR of 65.6% in this cohort.^[90]^[91]^[88] Tepotinib (Tepmetko), another type Ib ATP-competitive MET inhibitor, similarly targets the active kinase conformation with high selectivity, inhibiting MET phosphorylation with IC50 values of 1.7-1.8 nM in biochemical assays and showing minimal activity against a panel of 230-300 kinases at concentrations up to 1 μM. It possesses greater than 1,000-fold selectivity over other RTKs, including ALK, ROS1, and AXL. The FDA granted accelerated approval to tepotinib in February 2021 and traditional approval in February 2024 for adult patients with metastatic NSCLC harboring MET exon 14 skipping mutations. The phase II VISION trial reported an ORR of 46% (95% CI: 39-54) overall, rising to 57.3% in patients with high-confidence MET exon 14 mutations confirmed by liquid or tissue biopsy, with a median duration of response of 11.1 months and median progression-free survival of 8.5 months; long-term follow-up through 2023 maintained these outcomes, including an ORR of 58.6% in treatment-naïve subgroups.^[92]^[93]^[89] Despite initial efficacy, resistance to MET kinase inhibitors like capmatinib and tepotinib often develops through on-target mechanisms, including secondary MET kinase domain mutations that alter inhibitor binding. The solvent-front mutation G1163R, for instance, emerges post-treatment and reduces sensitivity by sterically hindering access to the ATP site, particularly impacting type I inhibitors; preclinical models show it confers resistance to capmatinib and tepotinib, necessitating sequential use of alternative agents such as type II inhibitors. Other common resistance alterations include D1228N and Y1230C/H, which similarly impair drug efficacy in MET exon 14-mutated NSCLC. Clinical data from 2023-2025 trials, including post-progression analyses, indicate that approximately 20-30% of resistant cases harbor such mutations, highlighting the need for mutation-specific next-line therapies.^[94]^[95]^[96]

HGF and MET Antagonists

Antagonists targeting hepatocyte growth factor (HGF) or the MET receptor extracellularly represent a class of therapeutics designed to block ligand-receptor interactions, thereby inhibiting MET signaling without directly affecting the intracellular kinase domain. These include monoclonal antibodies that neutralize HGF or bind MET to prevent dimerization and activation, as well as decoy receptors that trap HGF as ligand sinks. Unlike small-molecule kinase inhibitors, these agents focus on extracellular blockade, offering potential advantages in selectivity and reduced off-target effects in normal tissues expressing MET. Preclinical and clinical studies have explored their efficacy in MET-driven malignancies, particularly where HGF/MET axis hyperactivity promotes tumor growth, invasion, and metastasis. Anti-HGF antibodies, such as ficlatuzumab and rilotumumab, sequester HGF to inhibit its binding to MET. Ficlatuzumab, a humanized IgG1 monoclonal antibody, binds with high affinity to both pro-HGF and mature HGF, neutralizing the ligand and preventing proteolytic activation and subsequent MET stimulation. In a randomized phase II trial for pan-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), ficlatuzumab monotherapy yielded a median progression-free survival (PFS) of 1.8 months and objective response rate (ORR) of 4%, while combination with the EGFR inhibitor cetuximab improved median PFS to 3.7 months (P=0.04) and ORR to 19%, with enhanced responses in HPV-negative (ORR 38%, P=0.02) and c-Met-overexpressing subgroups, suggesting synergistic pathway inhibition. A phase III trial evaluating ficlatuzumab plus cetuximab is ongoing in similar HNSCC populations. Rilotumumab, another humanized monoclonal antibody, specifically targets mature HGF to block its interaction with MET. In the phase III RILOMET-1 trial for advanced MET-positive gastric or gastro-oesophageal junction cancer, rilotumumab combined with epirubicin, cisplatin, and capecitabine failed to improve overall survival (median 8.8 months vs. 10.7 months; hazard ratio 1.34, P=0.003) and was halted early due to increased mortality in the treatment arm, with no benefits observed across subgroups defined by MET expression or HGF levels. Despite earlier phase II signals of PFS extension in MET-high gastric cancer, rilotumumab development has been discontinued following these results. Anti-MET antibodies and decoy constructs directly engage the receptor to disrupt HGF-induced dimerization. Onartuzumab (MetMAb), a monovalent humanized antibody, binds the Sema domain (specifically blades 4–6) of MET, sterically hindering HGF association and receptor activation while avoiding agonistic effects through its monovalent design. The phase III METLUNG trial in previously treated MET-positive non-small cell lung cancer (NSCLC) randomized patients to onartuzumab plus erlotinib versus erlotinib alone, but showed no overall survival benefit (median 6.8 months vs. 9.1 months; hazard ratio 1.27, P=0.068) or PFS improvement (2.7 months vs. 2.6 months), leading to trial discontinuation for futility in 2014. Development of onartuzumab was subsequently halted due to these negative outcomes. Decoy MET approaches, exemplified by DN30 and its derivatives, utilize antibody-mediated receptor shedding or soluble extracellular fragments to deplete surface MET or trap HGF. The DN30 monoclonal antibody binds the IPT-4 domain of MET, triggering ADAM-10-dependent proteolytic shedding that reduces cell-surface receptor levels by up to 57% and inhibits HGF-induced phosphorylation, migration, and invasion in preclinical models. In vivo, DN30 suppresses primary tumor growth and spontaneous metastasis formation in MET-dependent xenografts, such as gastric and lung carcinoma models, with efficacy enhanced in humanized formats like hOA-DN30 that promote MET degradation and tumor remission. Soluble decoy MET fragments, such as C-terminal constructs or DN30-derived Fabs, further act as HGF traps, demonstrating preclinical antitumor activity in metastasis assays by sequestering ligand and preventing signaling. These decoy strategies remain primarily investigational, with ongoing efforts to improve pharmacokinetics for clinical translation.

Emerging Therapies

Passive immunotherapy strategies targeting the hepatocyte growth factor receptor (MET) have advanced into early clinical stages, focusing on bispecific antibodies and antibody-drug conjugates (ADCs) to enhance specificity and efficacy in MET-overexpressing solid tumors. Emibetuzumab (LY2875358), a bivalent humanized IgG4 monoclonal antibody, binds to MET with high affinity, blocking hepatocyte growth factor (HGF) binding and inducing receptor internalization and lysosomal degradation, thereby inhibiting both ligand-dependent and independent MET signaling. In phase I trials, emibetuzumab monotherapy was well-tolerated in patients with advanced solid tumors at doses up to 2000 mg, demonstrating preliminary antitumor activity, particularly in MET-amplified non-small cell lung cancer (NSCLC).^[97] Ongoing phase II evaluations, including combinations with erlotinib, continue to explore its role in EGFR-mutant NSCLC, with 2025 updates confirming stable disease in subsets of MET-dysregulated patients.^[98] Antibody-drug conjugates represent another passive approach, linking MET-targeting antibodies to cytotoxic payloads for targeted delivery. SHR-1826, a novel c-MET-directed ADC, has entered phase I testing in advanced solid tumors, showing dose-dependent tumor regression in preclinical models and manageable safety in initial human cohorts as of 2025.^[99] Similarly, ABBV-400, an ADC conjugating a MET-specific antibody to a topoisomerase I inhibitor payload, demonstrated encouraging responses in MET-amplified colorectal and other solid tumors in phase I studies, with objective response rates around 20% in heavily pretreated patients.^[100] Active immunotherapy modalities, such as chimeric antigen receptor (CAR) T cells targeting MET, offer promise for eliciting durable responses against MET-expressing malignancies. Preclinical studies have validated MET-specific CAR-T cells in suppressing tumor growth in MET-overexpressing models of NSCLC and hepatocellular carcinoma (HCC), with enhanced cytotoxicity observed through co-expression of dominant-negative TGF-β receptors to counter immunosuppressive signals.^[101] In chronic lymphocytic leukemia (CLL), where HGF/MET signaling supports leukemic cell survival via anti-apoptotic pathways, targeting this axis with immunotherapies like CAR-T holds potential, supported by 2025 preclinical data indicating reduced CLL proliferation upon MET inhibition.^[72] MET vaccines remain largely investigational, with limited clinical translation to date. Combination therapies integrating MET inhibition with immune checkpoint inhibitors (ICIs) address resistance mechanisms in NSCLC, where HGF/MET activation promotes an immunosuppressive tumor microenvironment and limits PD-1/PD-L1 blockade efficacy. A 2025 analysis revealed elevated HGF/MET signaling in ICI-resistant advanced NSCLC tumors, correlating with poorer progression-free survival; dual inhibition restored T-cell infiltration and enhanced response rates in preclinical models.^[102] Clinical trials combining MET inhibitors like capmatinib with PD-1 blockers (e.g., pembrolizumab) in MET-altered NSCLC, such as the phase II study in treatment-naïve PD-L1-high patients, did not demonstrate improved efficacy over pembrolizumab alone, highlighting challenges in this approach. Other MET TKIs, such as savolitinib and glumetinib, have received approval in China for MET exon 14 skipping NSCLC as of 2025, expanding global options for targeted therapy.^[103] Inhibitors of pro-HGF activation and gene-based therapies represent cutting-edge strategies to disrupt upstream MET signaling in specific contexts like liver disease. Pro-HGF activator inhibitors (HGFA-I), such as SRI31215, block the conversion of inactive pro-HGF to its bioactive form, reducing MET-driven invasion in fibroblast-rich tumor microenvironments; combined with MET kinase inhibitors, this approach yielded significant tumor reduction in castration-resistant prostate cancer liver metastasis models in 2025 studies.^[104] CRISPR/Cas9-mediated MET knockdown has demonstrated therapeutic potential in liver disease models, including HCC, where MET overexpression cooperates with TP53 loss to drive tumorigenesis—gene editing reduced tumor burden and fibrosis progression in preclinical xenografts.^[105] These combined modalities highlight opportunities for precision interventions in HGF/MET-dependent pathologies.