C-MET
Encyclopedia
c-Met is a proto-oncogene that encodes a protein
known as hepatocyte growth factor receptor (HGFR). The hepatocyte growth factor receptor 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.
MET is a membrane receptor that is essential for embryonic development and wound healing. Hepatocyte growth factor
(HGF) is the only known ligand of the MET receptor. MET is normally expressed by cells of epithelial origin, while expression of HGF is restricted to cells of mesenchymal
origin. Upon HGF stimulation, MET induces several biological responses that collectively give rise to a program known as invasive growth.
Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis
) that supply the tumor with nutrients, and cancer spread to other organs (metastasis
). 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.
Various mutations in the MET gene are associated with papillary renal carcinoma.
(RTK) 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.
, SHC, SRC
, and the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K), 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 (PLC-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.
pathways:
.
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
(EMT). 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. Furthermore, MET is required for such critical processes as liver
regeneration and wound healing
during adulthood.
, 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 (HIF1), which is activated by low concentration of intracellular oxygen. HIF1 can bind to one of the several hypoxia
response elements (HREs) in the MET promoter. Hypoxia also activates transcription factor AP-1, which is involved in MET transcription.
Coordinated down-regulation of both MET and its downstream effector extracellular signal-regulated kinase 2 (ERK2) by miR-199a*
may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.
(phosphatase and tensin homolog) is a tumor suppressor gene
encoding a protein PTEN, which possesses lipid and protein phosphatase-dependent as well as phosphatase-independent activities. PTEN protein phosphatase
is able to interfere with MET signaling by dephosphorylating either PIP3 generated by PI3K, or the p52 isoform of SHC
. SHC dephosphorylation inhibits recruitment of the GRB2
adapter to activated MET.
and increased MET signaling in renal cell carcinoma
(RCC).
binding to MET, thus inhibiting receptor transphosphorylation and recruitment of the downstream effectors. The limitations of kinase inhibitors include the facts that they only inhibit kinase-dependent MET activation, and that none of them is fully specific for MET.
. For this purpose, truncated HGF, anti-HGF neutralizing antibodies, and an uncleavable form of HGF have been utilized so far. The major limitation of HGF inhibitors is that they block only HGF-dependent MET activation.
in animal models.
can act either passively by enhancing the immunologic response to MET-expressing tumor cells, or actively by stimulating immune cells and altering differentiation/growth of tumor cells.
(mAbs) is a form of passive immunotherapy. MAbs facilitate destruction of tumor cells by complement
-dependent cytotoxicity (CDC) and cell-mediated cytotoxicity (ADCC). In CDC, mAbs bind to specific antigen
, leading to activation of the complement cascade, which in turn leads to formation of pores in tumor cells. In ADCC, the Fab domain of a mAb binds to a tumor antigen
, and Fc domain binds to Fc receptors present on effector cells (phagocytes and NK cells), thus forming a bridge between an effector and a target cells. This induces the effector cell activation, leading to phagocytosis of the tumor cell by neutrophils and macrophages. Furthermore, NK cells release cytotoxic molecules, which lyse tumor cells.
), which triggers non-specific stimulation of numerous immune cells. IFNs have been tested as therapies for many types of cancers and have demonstrated therapeutic benefits. IL-2 has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of renal cell carcinoma
and metastatic melanoma, which often have deregulated MET activity.
with Hepatocyte growth factor
, Cbl gene
, GLMN
, CDH1
, Grb2
and RANBP9
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
known as hepatocyte growth factor receptor (HGFR). The hepatocyte growth factor receptor 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.
MET is a membrane receptor that is essential for embryonic development and wound healing. Hepatocyte growth factor
Hepatocyte growth factor
Hepatocyte growth factor/scatter factor is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts on haemopoietic progenitor cells...
(HGF) is the only known ligand of the MET receptor. MET is normally expressed by cells of epithelial origin, while expression of HGF is restricted to cells of mesenchymal
Mesenchymal stem cell
Mesenchymal stem cells, or MSCs, are multipotent stem cells that can differentiate into a variety of cell types, including: osteoblasts , chondrocytes and adipocytes...
origin. Upon HGF stimulation, MET induces several biological responses that collectively give rise to a program known as invasive growth.
Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
) that supply the tumor with nutrients, and cancer spread to other organs (metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
). 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.
Various mutations in the MET gene are associated with papillary renal carcinoma.
Gene
MET proto-oncogene (GeneID: 4233) 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 kinaseReceptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
(RTK) that is produced as a single-chain precursor. The precursor is proteolytically cleaved at a furin
Furin
Furin is a protein that in humans is encoded by the FURIN gene. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR and therefore the protein was named 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 semaphorinSemaphorinSemaphorins are a class of secreted and membrane proteins that act as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. They are usually cues to deflect axons from inappropriate regions, especially...
s (Sema domain), which includes the full α-chain and the N-terminal part of the β-chain
- Cysteine-rich MET-related sequence (MRS domain)
- Glycine-proline-rich repeats (G-P repeats)
- Four immunoglobulin-like structures (Ig domains), a typical protein-protein interaction region.
Intracellular
A Juxtamembrane segment that contains:- a serine residue (Ser 985), which inhibits the receptor kinase activity upon phosphorylation
- a tyrosine (Tyr 1003), which is responsible for MET polyubiquitination, endocytosisEndocytosisEndocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, and degradation upon interaction with the ubiquitin ligaseUbiquitin ligaseA ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
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 (Tyr 1349 and Tyr 1356), which are inserted into the multisubstrate docking site, capable of recruiting downstream adapter proteins with Src homology-2SH2 domainThe SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
(SH2) 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 GRB2Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, SHC, SRC
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
, and the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K), 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 (PLC-γ), p85, and SHP2.
GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity
Avidity
In proteins, avidity is a term used to describe the combined strength of multiple bond interactions. Avidity is distinct from affinity, which is a term used to describe the strength of a single bond...
, 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 transductionSignal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways:
- The RAS pathway mediates HGF-induced scatteringScatteringScattering is a general physical process where some forms of radiation, such as light, sound, or moving particles, are forced to deviate from a straight trajectory by one or more localized non-uniformities in the medium through which they pass. In conventional use, this also includes deviation of...
and proliferationCell growthThe term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
signals, which lead to branching morphogenesis. Of note, HGF, differently from most mitogens, induces sustained RAS activation, and thus prolonged MAPKMitogen-activated protein kinaseMitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
activity.
- The PI3KPhosphoinositide 3-kinasePhosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
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 RAC1RAC1Ras-related C3 botulinum toxin substrate 1 also known as Rac1 is a protein that in humans is encoded by the RAC1 gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.- Function :Rac1 is...
and PAKPAK1Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.-Interactions:PAK1 has been shown to interact with C-Raf, NCK1, LIMK1, RAC1, ARHGEF2, BMX, ARPC1B, DYNLL1, Cyclin-dependent kinase 5, PAK1IP1 and CDC42....
. PI3K activation also triggers a survival signal due to activation of the AKTAKTAkt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
pathway.
- The STATSTAT proteinThe STAT protein regulates many aspects of growth, survival and differentiation in cells...
pathway, together with the sustained MAPK activation, is necessary for the HGF-induced branching morphogenesis. MET activates the STAT3STAT3Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
transcription factorTranscription factorIn molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
directly, through an SH2 domainSH2 domainThe SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
.
- The beta-cateninBeta-cateninBeta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
pathway, a key component of the Wnt signaling pathwayWnt signaling pathwayThe Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
, translocates into the nucleus following MET activation and participates in transcriptional regulation of numerous genes.
- The Notch pathway, through transcriptional activation of Delta ligand (see DLL3DLL3Delta-like 3 , also known as DLL3, is a protein which in humans is encoded by the DLL3 gene. Two transcript variants encoding distinct isoforms have been identified for this gene.- Function :...
).
Role in development
MET mediates a complex program known as invasive growth. Activation of MET triggers mitogenesis, and morphogenesisMorphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
.
During embryonic development, transformation of the flat, two-layer germinal disc
Germinal disc
-Birds:The germinal disc, also called the blastodisc, is a small, circular, white spot on the surface of the yellow yolk of a bird's egg.-Mammals:...
into a three-dimensional body depends on transition of some cells from an epithelial
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
to spindle-shaped cells with motile behaviour, a mesenchymal
Mesenchymal stem cell
Mesenchymal stem cells, or MSCs, are multipotent stem cells that can differentiate into a variety of cell types, including: osteoblasts , chondrocytes and adipocytes...
phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
. This process is referred to as epithelial-mesenchymal transition
Epithelial-mesenchymal transition
Epithelial-mesenchymal transition or transformation is a hypothesized program of development of biological cells characterized by loss of cell adhesion, repression of E-cadherin expression, and increased cell mobility...
(EMT). Later in embryonic development, MET is crucial for gastrulation
Gastrulation
Gastrulation is a phase early in the embryonic development of most animals, during which the single-layered blastula is reorganized into a trilaminar structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm.Gastrulation takes place after cleavage...
, angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, myoblast
Myoblast
A myoblast is a type of embryonic progenitor cell that gives rise to muscle cells .The muscle cells can be skeletal muscle, smooth muscle, and cardiac muscle....
migration, bone remodeling
Bone remodeling
Bone remodeling is a lifelong process where mature bone tissue is removed from the skeleton and new bone tissue is formed...
, and nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
sprouting among others. MET is essential for embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
, because MET -/- mice die in utero due to severe defects in placental development. Furthermore, MET is required for such critical processes as liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
regeneration and wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
during adulthood.
Tissue distribution
MET is normally expressed by epithelial cells. However, MET is also found on endothelial cells, neurons, hepatocytes, hematopoietic cells, and melanocytes. 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 EtsETS transcription factor family
In the field of molecular biology, the ETS family is one of the largest families of transcription factors and is unique to metazoans. There are 29 genes in humans, 28 in the mouse, 10 in Caenorhabditis elegans and 9 in Drosophila. The founding member of this family was identified as a gene...
, a family of transcription factors that control several invasive growth genes. ETS1
ETS1
Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene. The protein encoded by this gene belongs to the ETS family of transcription factors.-Interactions:ETS1 has been shown to interact with TTRAP, UBE2I and Death associated protein 6....
activates MET transcription in vitro. MET transcription is activated by hypoxia-inducible factor 1 (HIF1), which is activated by low concentration of intracellular oxygen. HIF1 can bind to one of the several hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
response elements (HREs) in the MET promoter. Hypoxia also activates transcription factor AP-1, which is involved in MET transcription.
Role in cancer
MET pathway plays an important role in the development of cancer through:- activation of key oncogenic pathways (RAS, PI3KPhosphoinositide 3-kinasePhosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
, STAT3STAT3Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
, beta-cateninBeta-cateninBeta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
);
- angiogenesisAngiogenesisAngiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
(sprouting of new blood vessels from pre-existing ones to supply a tumor with nutrients);
- scatter (cells dissociation due to metalloprotease production), which often leads to metastasisMetastasisMetastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
.
Coordinated down-regulation of both MET and its downstream effector extracellular signal-regulated kinase 2 (ERK2) by miR-199a*
Mir-199 microRNA precursor
The miR-199 microRNA precursor , is a short non-coding RNAgene involved in gene regulation.miR-192 and miR-215 have now been predicted or experimentally confirmed in mouse, human and a further 21 other species.....
may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.
PTEN
PTENPTEN (gene)
Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
(phosphatase and tensin homolog) is a tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
encoding a protein PTEN, which possesses lipid and protein phosphatase-dependent as well as phosphatase-independent activities. PTEN protein phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
is able to interfere with MET signaling by dephosphorylating either PIP3 generated by PI3K, or the p52 isoform of SHC
SHC1
SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells....
. SHC dephosphorylation inhibits recruitment of the GRB2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
adapter to activated MET.
VHL
There is evidence of correlation between inactivation of VHL tumor suppressor geneTumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
and increased MET signaling in renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
(RCC).
Cancer therapies targeting HGF/MET
Since tumor invasion and metastasis are the main cause of death in cancer patients, interfering with MET signaling appears to be a promising therapeutic approach.MET kinase inhibitors
Kinase inhibitors are low molecular weight molecules that prevent ATPAdenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
binding to MET, thus inhibiting receptor transphosphorylation and recruitment of the downstream effectors. The limitations of kinase inhibitors include the facts that they only inhibit kinase-dependent MET activation, and that none of them is fully specific for MET.
- K252aK252aK252a is an alkaloid isolated from Nocardiopisis sp. soil fungi. This staurosporine analog is a highly potent cell permeable inhibitor of CaM kinase and phosphorylase kinase...
(FermentekFermentekFermentek Ltd. is a biotechnological company, located in Atarot industrial zone, Jerusalem, Israel, specializing in the research, development and manufacture of biologically active, natural products isolated from microorganisms as well as from other natural sources such as plants and algae.The main...
Biotechnology) is a staurosporineStaurosporineStaurosporine is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus.It was the first of over 50 alkaloids to be isolated with this type of bis-indole chemical structure...
analogue isolated from Nocardiopsis sp. soil fungi, and it is a potent inhibitor of all receptor tyrosine kinases (RTKs). At nanomolar concentrations, K252a inhibits both the wild typeWild typeWild type refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard, "normal" allele at a locus, in contrast to that produced by a non-standard, "mutant" allele...
and the mutant (M1268T) MET function.
- SU11274 (SUGENSUGENSUGEN was a drug discovery company focused on development of protein kinase inhibitors. It was founded in 1991, and shut down in 2003, after pioneering protein kinases as therapeutic targets and developing the successful cancer therapy sunitinib .-Early history and focus:Sugen was founded in 1991...
) specifically inhibits MET kinase activity and its subsequent signaling. SU11274 is also an effective inhibitor of the M1268T and H1112Y MET mutants, but not the L1213V and Y1248H mutants. SU11274 has been demonstrated to inhibit HGF-induced motility and invasion of epithelial and carcinoma cells.
- PHA-665752 (PfizerPfizerPfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
) specifically inhibits MET kinase activity, and it has been demonstrated to represses both HGF-dependent and constitutive MET phosphorylation. Furthermore, some tumors harboring MET amplifications are highly sensitive to treatment with PHA-665752. - ARQ197 (ArQule) is a promising selective inhibitor of MET, which has entered a phase 2 clinical trial in 2008.
- ForetinibForetinibForetinib is an experimental drug candidate for the treatment of cancer. It was discovered by Exelixis and is under development by GlaxoSmithKline. It is currently in Phase II clinical trials....
(XL880, Exelixis) targets multiple receptor tyrosine kinases (RTKs) with growth-promoting and angiogenic properties. The primary targets of foretinib are MET, VEGFR2, and KDRKinase insert domain receptorKinase insert domain receptor also known as vascular endothelial growth factor receptor 2 is a VEGF receptor. KDR is the human gene encoding it. KDR has also been designated as CD309...
. Foretinib has completed a phase 2 clinical trials with indications for papillary renal cell carcinomaRenal cell carcinomaRenal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
, gastric cancer, and head and neck cancerHead and neck cancerHead and neck cancer refers to a group of biologically similar cancers that start in the upper aerodigestive tract, including the lip, oral cavity , nasal cavity , paranasal sinuses, pharynx, and larynx. 90% of head and neck cancers are squamous cell carcinomas , originating from the mucosal lining...
(see Poster). - SGX523 (SGX Pharmaceuticals) specifically inhibits MET at low nanomolar concentrations. (See Poster.)
- MP470 (SuperGen) is a novel inhibitor of c-KIT, MET, PDGFR, Flt3, and AXLAXL receptor tyrosine kinaseTyrosine-protein kinase receptor UFO is an enzyme that in humans is encoded by the AXL gene.-Interactions:AXL receptor tyrosine kinase has been shown to interact with TENC1.-Further reading:...
. Phase I clinical trial of MP470 had been announced in 2007. (See Poster.)
HGF inhibitors
Since HGF is the only known ligand of MET, formation of a HGF:MET complex blocks MET biological activityBiological activity
In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or pharmacophore but can be modified by the other...
. For this purpose, truncated HGF, anti-HGF neutralizing antibodies, and an uncleavable form of HGF have been utilized so far. The major limitation of HGF inhibitors is that they block only HGF-dependent MET activation.
- NK4 competes with HGF as it binds MET without inducing receptor activation, thus behaving as a full antagonistAntagonistAn antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
. NK4 is a molecule bearing the N-terminal hairpin and the four kringle domains of HGF. Moreover, NK4 is structurally similar to angiostatins, which is why it possesses anti-angiogenic activity.
- Neutralizing anti-HGF antibodies were initially tested in combination, and it was shown that at least three antibodies, acting on different HGF epitopes, are necessary to prevent MET tyrosine kinase activation. More recently, it has been demonstrated that fully human monoclonal antibodiesMonoclonal antibodiesMonoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
can individually bind and neutralize human HGF, leading to regression of tumors in mouse models. Two anti-HGF antibodies are currently available: the humanized AV299 (AVEO), and the fully human AMG102 (AmgenAmgenAmgen Inc. is an international biotechnology company headquartered in Thousand Oaks, California. Located in the Conejo Valley, Amgen is the world's largest independent biotech firm. The company employs approximately 17,000 staff members. Its products include Epogen, Aranesp, Enbrel, Kineret,...
).
- Uncleavable HGF is an engineered form of pro-HGF carrying a single amino-acid substitution, which prevents the maturation of the molecule. Uncleavable HGF is capable of blocking MET-induced biological responses by binding MET with high affinity and displacing mature HGF. Moreover, uncleavable HGF competes with the wild-type endogenous pro-HGF for the catalytic domain of proteases that cleave HGF precursors. Local and systemic expression of uncleavable HGF inhibits tumor growth and, more importantly, prevents metastasisMetastasisMetastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
.
Decoy MET
Decoy MET refers to a soluble truncated MET receptor. Decoys are able to inhibit MET activation mediated by both HGF-dependent and independent mechanisms, as decoys prevent both the ligand binding and the MET receptor homodimerization. CGEN241 (Compugen) is a decoy MET that is highly efficient in inhibiting tumor growth and preventing metastasisMetastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
in animal models.
Immunotherapy targeting MET
Drugs used for immunotherapyImmunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
can act either passively by enhancing the immunologic response to MET-expressing tumor cells, or actively by stimulating immune cells and altering differentiation/growth of tumor cells.
Passive immunotherapy
Administering monoclonal antibodiesMonoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
(mAbs) is a form of passive immunotherapy. MAbs facilitate destruction of tumor cells by complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
-dependent cytotoxicity (CDC) and cell-mediated cytotoxicity (ADCC). In CDC, mAbs bind to specific antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
, leading to activation of the complement cascade, which in turn leads to formation of pores in tumor cells. In ADCC, the Fab domain of a mAb binds to a tumor antigen
Tumor antigen
Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful in identifying tumor cells and are potential candidates for use in cancer therapy.- Mechanism of tumor antigenesis:...
, and Fc domain binds to Fc receptors present on effector cells (phagocytes and NK cells), thus forming a bridge between an effector and a target cells. This induces the effector cell activation, leading to phagocytosis of the tumor cell by neutrophils and macrophages. Furthermore, NK cells release cytotoxic molecules, which lyse tumor cells.
- DN30 is monoclonal anti-MET antibody that recognizes the extracellular portion of MET. DN30 induces both shedding of the MET ectodomainEctodomainAn ectodomain is the domain of a membrane protein that extends into the extracellular space . Ectodomains are usually the part of a protein that initiate contact with surface which leads to signal transduction. In SARS-CoV the ectodomain of the spike protein is responsible for attachment to and...
as well as cleavage of the intracellular domain, which is successively degraded by proteasomeProteasomeProteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
machinery. As a consequence, on one side MET is inactivated, and on the other side the shed portion of extracellular MET hampers activation of other MET receptors, acting as a decoy. DN30 inhibits tumour growth and prevents metastasisMetastasisMetastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
in animal models.
- OA-5D5 is one-armed monoclonal anti-MET antibody that was demonstrated to inhibit orthotopic pancreatic and glioblastoma tumor growth and to improve survival in tumor xenograft models. OA-5D5 is produced as a recombinant protein in Escherichia coli. It is composed of murine variable domains for the heavy and light chains with human IgG1 constant domains. The antibody blocks HGF binding to MET in a competitive fashion.
Active immunotherapy
Active immunotherapy to MET-expressing tumors can be achieved by administering cytokines, such as interferons (IFNs) and interleukins (IL-2Interleukin 2
Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
), which triggers non-specific stimulation of numerous immune cells. IFNs have been tested as therapies for many types of cancers and have demonstrated therapeutic benefits. IL-2 has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
and metastatic melanoma, which often have deregulated MET activity.
Interactions
Met has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Hepatocyte growth factor
Hepatocyte growth factor
Hepatocyte growth factor/scatter factor is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts on haemopoietic progenitor cells...
, Cbl gene
Cbl gene
Cbl is a mammalian gene encoding several proteins including E3 ubiquitin-protein ligase CBL involved in cell signalling and protein ubiquitination...
, GLMN
GLMN
Glomulin is a protein that in humans is encoded by the GLMN gene.-Interactions:GLMN has been shown to interact with FKBP52, C-Met and FKBP1A.-Further reading:...
, CDH1
CDH1 (gene)
Cadherin-1 also known as CAM 120/80 or epithelial cadherin or uvomorulin is a protein that in humans is encoded by the CDH1 gene. CDH1 has also been designated as CD324 . It is a tumor suppressor gene.- Function :Cadherin-1 is a classical member of the cadherin superfamily...
, Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
and RANBP9
RANBP9
Ran-binding protein 9 is a protein that in humans is encoded by the RANBP9 gene.-Interactions:RANBP9 has been shown to interact with C-Met, DYRK1B, USP11, DISC1, Androgen receptor, Glucocorticoid receptor, S100A7, HIPK2 and MKLN1.-Further reading:...
.
External links
- UniProtKB/Swiss-Prot entry P08581: MET_HUMAN, ExPASy (Expert Protein Analysis System) proteomics server of the Swiss Institute of Bioinformatics (SIB).
- Tpr-met fusion proteinTpr-met fusion proteinTpr-met fusion protein is an oncogene fusion protein consisting of TPR and MET....
- A table with references to significant roles of MET in cancer.