Hepatocyte growth factor receptor

Hepatocyte growth factor receptor is a protein that in humans is encoded by the MET gene. The protein possesses tyrosine kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor.
HGF receptor is a single pass tyrosine kinase receptor essential for embryonic development, organogenesis and wound healing. Hepatocyte growth factor/scatter factor and its splicing isoform are the only known ligands of the HGF receptor. MET is normally expressed by cells of epithelial origin, while expression of HGF/SF is restricted to cells of mesenchymal origin. When HGF/SF binds its cognate receptor MET it induces its dimerization through a not yet completely understood mechanism leading to its activation.
Sometimes MET is misunderstood as of an abbreviation of mesenchymal-epithelial transition. It is incorrect. The three letters of MET come from N-methyl-N'-nitro-N-nitrosoguanidine.
Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels that supply the tumor with nutrients, and cancer spread to other organs. MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Normally, only stem cells and progenitor cells express MET, which allows these cells to grow invasively in order to generate new tissues in an embryo or regenerate damaged tissues in an adult. However, cancer stem cells are thought to hijack the ability of normal stem cells to express MET, and thus become the cause of cancer persistence and spread to other sites in the body. Both the overexpression of Met/HGFR, as well as its autocrine activation by co-expression of its hepatocyte growth factor ligand, have been implicated in oncogenesis.
Various mutations in the MET gene are associated with papillary renal carcinoma.

Gene

MET proto-oncogene has a total length of 125,982 bp, and it is located in the 7q31 locus of chromosome 7. MET is transcribed into a 6,641 bp mature mRNA, which is then translated into a 1,390 amino-acid MET protein.

Protein

MET is a receptor tyrosine kinase that is produced as a single-chain precursor. The precursor is proteolytically cleaved at a furin site to yield a highly glycosylated extracellular α-subunit and a transmembrane β-subunit, which are linked together by a disulfide bridge.

Extracellular

Region of homology to semaphorins, which includes the full α-chain and the N-terminal part of the β-chain
Cysteine-rich MET-related sequence
Glycine-proline-rich repeats
Four immunoglobulin-like structures, a typical protein-protein interaction region.
Intracellular

A juxtamembrane segment that contains:

A serine residue, which inhibits the receptor kinase activity upon phosphorylation
A tyrosine residue, which is responsible for MET polyubiquitination, endocytosis, and degradation upon interaction with the ubiquitin ligase CBL
Tyrosine kinase domain, which mediates MET biological activity. Following MET activation, transphosphorylation occurs on Tyr 1234 and Tyr 1235
C-terminal region contains two crucial tyrosines, which are inserted into the multisubstrate docking site, capable of recruiting downstream adapter proteins with Src homology-2 domains. The two tyrosines of the docking site have been reported to be necessary and sufficient for the signal transduction both in vitro.
MET signaling pathway

MET activation by its ligand HGF induces MET kinase catalytic activity, which triggers transphosphorylation of the tyrosines Tyr 1234 and Tyr 1235. These two tyrosines engage various signal transducers, thus initiating a whole spectrum of biological activities driven by MET, collectively known as the invasive growth program. The transducers interact with the intracellular multisubstrate docking site of MET either directly, such as GRB2, SHC, SRC, and the p85 regulatory subunit of phosphatidylinositol-3 kinase, or indirectly through the scaffolding protein Gab1
Tyr 1349 and Tyr 1356 of the multisubstrate docking site are both involved in the interaction with GAB1, SRC, and SHC, while only Tyr 1356 is involved in the recruitment of GRB2, phospholipase C γ, p85, and SHP2.
GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity. Upon interaction with MET, GAB1 becomes phosphorylated on several tyrosine residues which, in turn, recruit a number of signalling effectors, including PI3K, SHP2, and PLC-γ. GAB1 phosphorylation by MET results in a sustained signal that mediates most of the downstream signaling pathways.

Activation of signal transduction

MET engagement activates multiple signal transduction pathways:

The RAS pathway mediates HGF-induced scattering and proliferation signals, which lead to branching morphogenesis. Of note, HGF, differently from most mitogens, induces sustained RAS activation, and thus prolonged MAPK activity.
The PI3K pathway is activated in two ways: PI3K can be either downstream of RAS, or it can be recruited directly through the multifunctional docking site. Activation of the PI3K pathway is currently associated with cell motility through remodeling of adhesion to the extracellular matrix as well as localized recruitment of transducers involved in cytoskeletal reorganization, such as RAC1 and PAK. PI3K activation also triggers a survival signal due to activation of the AKT pathway.
The STAT pathway, together with the sustained MAPK activation, is necessary for the HGF-induced branching morphogenesis. MET activates the STAT3 transcription factor directly, through an SH2 domain.
The beta-catenin pathway, a key component of the Wnt signaling pathway, translocates into the nucleus following MET activation and participates in transcriptional regulation of numerous genes.
The Notch pathway, through transcriptional activation of Delta ligand.
Role in development

MET mediates a complex program known as invasive growth. Activation of MET triggers mitogenesis, and morphogenesis.
During embryonic development, transformation of the flat, two-layer germinal disc into a three-dimensional body depends on transition of some cells from an epithelial phenotype to spindle-shaped cells with motile behaviour, a mesenchymal phenotype. This process is referred to as epithelial-mesenchymal transition. Later in embryonic development, MET is crucial for gastrulation, angiogenesis, myoblast migration, bone remodeling, and nerve sprouting among others. MET is essential for embryogenesis, because MET ^−/− mice die in utero due to severe defects in placental development. Along with Ectodysplasin A, it has been shown to be involved in the differentiation of anatomical placodes, precursors of scales, feathers and hair follicles in vertebrates. Furthermore, MET is required for such critical processes as liver regeneration and wound healing during adulthood.
HGF/MET axis is also involved in myocardial development. Both HGF and MET receptor mRNAs are co-expressed in cardiomyocytes from E7.5, soon after the heart has been determined, to E9.5. Transcripts for HGF ligand and receptor are first detected before the occurrence of cardiac beating and looping, and persist throughout the looping stage, when heart morphology begins to elaborate. In avian studies, HGF was found in the myocardial layer of the atrioventricular canal, in a developmental stage in which the epithelial to mesenchymal transformation of the endocardial cushion occurs. However, MET is not essential for heart development, since α-MHCMet-KO mice show normal heart development.

Expression

Tissue distribution

MET is normally expressed by epithelial cells. However, MET is also found on endothelial cells, neurons, hepatocytes, hematopoietic cells, melanocytes and neonatal cardiomyocytes. HGF expression is restricted to cells of mesenchymal origin.

Transcriptional control

MET transcription is activated by HGF and several growth factors. MET promoter has four putative binding sites for Ets, a family of transcription factors that control several invasive growth genes. ETS1 activates MET transcription in vitro. MET transcription is activated by hypoxia-inducible factor 1, which is activated by low concentration of intracellular oxygen. HIF1 can bind to one of the several hypoxia response elements in the MET promoter. Hypoxia also activates transcription factor AP-1, which is involved in MET transcription.

Clinical significance

Role in cancer

MET pathway plays an important role in the development of cancer through:

activation of key oncogenic pathways ;
angiogenesis ;
scatter, which often leads to metastasis.

Coordinated down-regulation of both MET and its downstream effector extracellular signal-regulated kinase 2 by miR-199a* may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.
MET amplification has emerged as a potential biomarker of the clear cell tumor subtype.
The amplification of the cell surface receptor MET often drives resistance to anti-EGFR therapies in colorectal cancer.

Role in autism

The SFARIgene database lists MET with an autism score of 2.0, which indicates that it is a strong candidate for playing a role in cases of autism. The database also identifies at least one study that found a role for MET in cases of schizophrenia. The gene was first implicated in autism in a study that identified a polymorphism in the promoter of the MET gene. The polymorphism reduces transcription by 50%. Further, the variant as an autism risk polymorphism has been replicated, and shown to be enriched in children with autism and gastrointestinal disturbances. A rare mutation has been found that appears in two family members, one with autism and the other with a social and communication disorder. The role of the receptor in brain development is distinct from its role in other developmental processes. Activation of the MET receptor regulates synapse formation and can impact the development and function of circuits involved in social and emotional behavior.