Hepatocyte Growth Factor Receptor
Structure and Biosynthesis
The gene encoding for the MET receptor is located on chromosome 7q31. The primary MET transcript produces a 150-kDa polypeptide, which constitutes the 170-kDa-precursor protein after glycosylation. This precursor is further glycosylated and then cleaved into the α- and β-chains. Moreover, the HGF encoding gene is located in the same chromosomal region of MET receptor (chromosome 7q21.1).
Finally, the production of active HGF ligand is also controlled and limited. In particular, inhibitors of the HGF proteases, which are involved in the maturation of HGF ligand, have been identified.
Tissue Homeostasis and Morphogenesis
The HGF receptor is expressed at the cell surface in the epithelial cells of many organs, including the skin, liver, mammary gland, pancreas, prostate, kidney, muscle, and bone marrow. Targeted deletion of either HGF or MET receptor gene during embryonic development has showed that HGF mediates a signal exchange between mesenchymal and epithelial cells, which is essential for placental trophoblasts and hepatocytes (Schmidt et al. 1995; Uehara et al. 1995; Bladt et al. 1995). In addition, MET plays an essential role in the migration and survival of migratory muscle progenitors which colonize long distance sites such as limbs, diaphragm, and tongue, giving rise to the hypaxial muscles (Bladt et al. 1995). Knock-in mice bearing phenylalanine substitutions in place of the tyrosines in the multifunctional docking site display a loss-of-function phenotype similar to that of mice entirely lacking HGF or MET (Maina et al. 1996), indicating that the docking site is essential to transduce the HGF signal in vivo. The Gab1 knockout phenocopied the defects that were observed in HGF and MET null embryos, confirming the Gab1 essential role in MET-based signal transduction pathways (Sachs et al. 2000). Finally, the process of axon guidance in the developing nervous system is driven by both HGF and their cousins, semaphorins (Trusolino and Comoglio 2002). Tissue-specific MET conditional knockouts have shown that MET contributes to the homeostasis of liver, skeletal and cardiac muscle, pancreas, kidney, and brain also in adulthood (for a review, see Matsumoto et al. (2014)). In endothelial cells, HGF promotes the formation of capillary-like structures during angiogenesis (Bussolino et al. 1992). These apparently different functions may be reunified in the complex events orchestrated by HGF-MET axis for branching morphogenesis, which involves – besides survival and proliferation – cell shape changes, cytoskeleton reorganization, asymmetric polarization of the cells in the direction of branching, cell elongation, cell–cell contact dissociation and reassociation, extracellular matrix (ECM) remodeling, basement membrane, matrigel or collagen invasion, and cell motility.
Tissue Repair and Organ Regeneration
Tissue fibrosis is the final common outcome of organs withstanding chronic and sustained injury. In response to stress and damage, a wound-healing process starts to repair and recover the affected tissue. These reparative mechanisms include induction of the inflammatory response, activation of fibroblasts to produce ECM, and regeneration of damaged tissue through stimulation of stem/progenitor cells proliferation, migration, and differentiation. However, chronic injuries may lead to a maladaptive response with overproduction of ECM causing fibrotic lesions and tissue scar. Growing evidence indicates that HGF possesses a potent anti-fibrotic activity in different pathological contexts, such as ischemic cardiac damage and chronic renal and liver fibrosis. In vivo deletion of MET receptor in renal tubular cells increases apoptosis and interstitial fibrosis after kidney injury. MET deletion in hepatocytes causes defective liver regeneration and increased susceptibility to fibrosis and inflammation after hepatectomy or liver injury. Thus, MET signaling provides anti-apoptotic stimuli for organ repair. The anti-fibrotic activity of HGF-MET axis is largely due to its ability to antagonize TGF-β, the principal culprit of fibrosis, which is secreted in the damaged organ and stimulates myofibroblasts to deposit collagen in the ECM.
Stem cells are found in the adult organism and act as a repair system for the body. These stem/progenitor cells may remain quiescent (nondividing) for long periods of time until they are activated by a normal need for more cells to maintain tissues or by a disease or a tissue injury. The MET receptor is expressed in these cells. HGF, which is released by the injured ECM, activates them (oval cells in the liver, satellite cells in skeletal muscle, etc.) in their “niches,” guides their migration into the site of injury, and stimulates their expansion, survival, and differentiation. Thus, stem cells or progenitor cells, in damaged organs, exploit the MET-driven morphogenetic program, which is active during embryogenesis, and enhance tissue regeneration. Monocytes, macrophages, and monocyte-derived dendritic cells also express the MET receptor, while platelets, neutrophils, and mast cells produce HGF during regenerative processes, indicating a role of HGF-MET in immune regulation and inflammation. The protective action of HGF is at most explained by its ability to prevent cell death against various types of stress and injury, but it also seems to be associated with suppression of inflammation. Thus, enhancement of MET-mediated signaling may have a therapeutic meaning for the treatment of different types of diseases involving tissue injury in the liver and gastrointestinal, kidney, respiratory, cardiovascular, musculoskeletal, skin, and nervous system diseases (for a review, see Matsumoto et al. (2014)) (Fig. 5).
Function in Diseases
One of the main mechanisms for the metastatic behavior relies on the hypoxia-induced genes, which regulate angiogenesis, tumor vascularization, invasion, drug resistance, and metastasis. In 2003, Pennacchietti et al. discovered that the MET promoter contains several responsive elements that bind the hypoxia inducible factor (HIF), a transcription factor activated by low oxygen tension. Thus, in metabolically active tumors, the adaptation to low oxygen induces MET overexpression and promotes tumor migration and invasion as a mechanism of escape in search of oxygen. Another expedient used by tumor cells to disseminate in the body utilizes blood coagulation, as fibrin provides a scaffold for anchorage and invasion. In 2005, Boccaccio et al. showed that the MET oncogene activation leads to the hemostasis perturbation by upregulation of plasminogen activator inhibitor type 1 and cyclooxygenase-2, which induces migratory routes for invasive growth. In the majority of tumors, MET is overexpressed to help cells survive in conditions of stress, as it happens in tissue or organ injury. The cancer antiproliferative-targeted therapies, radiotherapy or anti-angiogenic agents, may select MET-amplified cancer cells or MET-expressing stem/progenitor cells which repair the cancer tissue damage. In cancer stem cells, not only amplification but also MET physiological expression inherited from the cell of origin (a stem/progenitor) can contribute to tumorigenesis and therapeutic resistance, by sustaining the inherent self-renewing, self-preserving, and invasive growth phenotype (Boccaccio and Comoglio 2014).
A polymorphism in the promoter region of the MET gene, known to decrease MET expression, was found to be genetically linked with autism (Campbell et al. 2006). Much less is known about the function of MET in brain diseases than about its role in cancer biology. HGF-MET axis promotes survival and migration of sensory neuron, motor neurons, and sympathetic neurons in embryonic development (Maina and Klein 1999). In addition, a role played by MET in the migration and survival of specialized interneurons of the cerebral cortex, cerebellum, and olfactory bulb has been shown (Powell et al. 2001; Giacobini et al. 2007; Ieraci et al. 2002). Thus, it is plausible that MET alteration leads to disturbed neuronal migration during early gestation. In cultured neuronal cells, HGF enhances neurite extension and branching, maturation of the dendritic spine and synaptic plasticity in the hippocampus, as well as synaptic long-term potentiation (LTP) in the CA1 region of the hippocampus (Akimoto et al. 2004; Qiu et al. 2014). Accordingly, the HGF-MET axis contributes to the activity-dependent regulation of physiological learning and memory performance in the adult brain (Kato et al. 2012). Genetic deletion of MET in pyramidal neurons showed alteration of synaptic development in specific excitatory hyperconnectivity circuits that may underlie social behavior and communication (Qiu et al. 2011). However, the exact mechanism of action of MET in these neurons remains elusive.
Stimulation of HGF receptor (MET) evokes a unique set of biological responses known as “invasive growth,” which are exploited during embryonic development, organ regeneration, and cancer. Although the MET downstream intracellular signaling events have been identified, they are not MET specific, since they have been found activated also by other growth factor receptors. It appears that the synchronous activation of the various pathways is critical for the completion of the invasive growth program. Moreover, spatial and temporal differences in signal intensity and duration may account for the specific biological outcome. Indeed, the subcellular compartmentalization of activated MET and the multiple regulatory systems used by the cell to downregulate MET may finely tune the RTK action and define the duration of the signal.
Over the last two decades, HGF receptor has become one of the most highly investigated cancer genes. In cancer, enhanced activation of MET is achieved through strategies such as activating point mutations, oncogenic translocation, and gene amplification. These strategies lead to constitutive activated forms of MET that escape regulatory mechanisms, which normally modulate signaling intensity and duration. Different MET inhibitors have been approved for clinical use in cancer and are being evaluated for their efficacy in MET-driven tumors. MET-targeted therapy may also benefit patients whose tumors have selected MET amplification as a mechanism of resistance to therapies attacking other regulators of cell proliferation such as EGFR. Whether MET inhibitors will be efficacious against tumors treated with radiotherapy or conventional chemotherapy in cases where MET is activated as an adaptive response to stressful conditions is still an outstanding question. On the other side of the coin based on studies using cell-/tissue-specific disruption of functional MET and preclinical disease models in experimental animals, there is evidence that HGF or agents with MET agonistic activity may have beneficial effects to contrast fibrosis and repair organs after injury damage in various clinical contexts. The challenge for the therapeutic use of MET-activating compounds in regenerative medicine is to envision bioactive molecules able to uncouple MET intrinsic ability of wound healing from those properties promoting full-blown invasive growth.