Disease relevance of Met

• These findings are consistent with the possibility that HGF-Met protein interaction is one of the molecular mechanisms promoting the vascularization of papillary carcinoma of the thyroid [1].
• We investigated the biochemical and biological effects of the tyrosine kinase inhibitor RPI-1 on the human lung cancer cell lines H460 and N592, which express constitutively active Met [2].
• Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model [3].
• We also identified an Egr-1-binding site in the mouse CD44 gene promoter that accounts for its responsiveness to HGF/SF in melanoma cells [4].
• It is also known that delivery of the human HGF gene cloned in a plasmid under a CMV promoter results in hepatomegaly in mice [5].

Psychiatry related information on Met

• Deregulated receptor tyrosine kinase signaling, which is another important feature of human melanoma, leads to spontaneous development of metastatic melanoma after a long latency period in mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF mice) [6].
• Genetically engineered mice lacking HGF/SF die in utero due to a failure of placental and hepatocyte differentiation, but little information exists regarding the expression of this signaling system in human development [7].

High impact information on Met

• In the presence of an alpha6beta4 mutant defective for Shc recruitment, Met cannot sustain HGF-mediated responses [8].
• The role of these genes in the patterning of limb muscles is unknown, although mutation of Pax3 or Met causes disruption of limb muscle development at an initial step, disturbing the epithelial-to-mesenchymal transition of the somitic epithelium [9].
• Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development [10].
• Hepatocyte growth factor (HGF) and its receptor, the Met tyrosine kinase, are determinants of placenta, liver, and muscle development [10].
• While the met proto-oncogene locus expresses the 9.0 kb RNA and maps to human chromosome 7q21-31, the locus expressing the 10.0 kb RNA, (tpr; translocated promoter region) maps to human chromosome 1 [11].

Chemical compound and disease context of Met

• Rat HGF cDNA, expressed under the control of a cytomegalovirus promoter, was transfected together with the neomycin resistance gene (PSV2neo) into MLE-10 cells by the calcium phosphate method, and propagated G418-resistant colonies were harvested colony by colony [12].
• In vitro, HGF expression was evaluated in isolated murine ATII cells and in 12 ADC cell lines, and we found that nicotine activated HGF expression in ATII cells and lung cancer cells [13].
• Analysis of genomic DNA of 126 lung adenocarcinoma patients for the Met juxtamembrane domain revealed the same Arg/Cys variation at the mouse homologous position in one patient; two other patients carried additional variants in the same domain, suggesting a potential role for rare MET juxtamembrane variants in human lung cancer [14].
• Similar HGF/SF treatment of cysts derived from cells expressing NH2-terminal deleted beta-catenins resulted in cells that proliferated but formed cell aggregates (polyps) within the cyst rather than tubules [15].
• Administration of LPS + GalN, without HGF, rapidly led to massive hepatocyte apoptosis and severe liver injury, and all mice died of hepatic failure within 8 hours [16].

Biological context of Met

• The transcriptional activator PAX3-FKHR rescues the defects of Pax3 mutant mice but induces a myogenic gain-of-function phenotype with ligand-independent activation of Met signaling in vivo [17].
• The Met mutation also increased sympathetic neuroblast apoptosis in vivo [18].
• Here, we use conditional mutagenesis in mice to analyze the function of Met during liver regeneration, using the Mx-cre transgene to introduce the mutation in the adult [19].
• Comparison of signal transduction pathways in control and mutant livers indicates that Met and other signaling receptors cooperate to fully activate particular signaling molecules, for instance, the protein kinase Akt [19].
• Analysis of cell cycle progression of hepatocytes in conditional Met mutant mice indicates a defective exit from quiescence and diminished entry into S phase [19].

Anatomical context of Met

• Similar results were obtained with NIH 3T3 cells expressing the fusion protein Trk-Met and stimulated with nerve growth factor, the Trk ligand [20].
• Moreover, late passage fibroblast cell lines established from p53-deficient animals overexpress Met and can be tumorigenic in athymic nude mice, suggesting that progression occurs in vitro [21].
• Addition of heparin to HSGAG-deficient CHO cells not only restored ligand binding, but also increased ligand-dependent Met tyrosine phosphorylation and c-fos expression [22].
• NGF-stimulation of mouse fibroblasts expressing tagged versions of both Trk-Met and Gab1 with NGF resulted in anchorage-independent growth and enhanced invasiveness [23].
• HGF greatly enhanced the neurite outgrowth of NGF-dependent sympathetic neurons throughout development [18].

Associations of Met with chemical compounds

• Heparin binding and oligomerization of hepatocyte growth factor/scatter factor isoforms. Heparan sulfate glycosaminoglycan requirement for Met binding and signaling [22].
• A C2 clone expressing simultaneously both h-met and h-HGF/SF is able to grow in soft agar and shows a decrease in myogenic potential comparable to that promoted by p65(tpr-met) kinase [24].
• In this study, we demonstrate that the amino-terminal (N) domain retains the heparin-binding properties of full-length HGF/SF [22].
• HGF/SF consists of a series of structural units, including an amino-terminal segment with a hairpin loop, four kringle domains, and a serine protease-like region [22].
• Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine [25].

Enzymatic interactions of Met

• HGF is secreted as an inactive zymogen and must be cleaved by a serine protease to initiate Met signaling [26].

Regulatory relationships of Met

• Thus, the loss of wild-type p53 appears to greatly enhance the opportunity for inappropriate Met expression [21].
• In both M23 and MM55 cells, HGF induces association with MET/HGFR and increased tyrosine phosphorylation of the SH2-domain containing proteins PI3K, GAP and NCK [27].
• FGF-2 also induced HGF/SF polypeptide synthesis [28].
• We now report that expression of the mutant presenilin-1 in these mice induces early and exaggerated increase in Par-4 expression in hippocampal neurons following glucose deprivation (an insult relevant to the pathogenesis of AD) [29].
• Both HGF-induced DNA fragmentation and caspase-3 activity were completely inhibited by co-incubation with an inhibitor of caspase-3, Ac-DEVD-H [30].

Other interactions of Met

• The spatial patterns of migratory interneurons reflect the complementary expression of hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, MET, in the forebrain [31].
• On distal chromosome 18 and on centromere of chromosome 6, we have mapped two pulmonary adenoma resistance loci (Par2 and Par4, respectively), which reduce lung tumor multiplicity strongly, up to 15-fold [32].
• We conclude that parallel but independent cues converge on the migratory hypaxial precursors in the dermomyotomal lip after they are laid down: a signal given by SF/HGF that controls the emigration of the precursors, and an as yet unidentified signal that controls Lbx1 [33].
• However, activation of the Erk1/2 kinase during liver regeneration depends exclusively on Met [19].
• It was previously shown that, like the oncogenic tpr-met, the mouse met proto-oncogene transforms NIH 3T3 cells [34].

Analytical, diagnostic and therapeutic context of Met

• After partial hepatectomy in mice carrying the Mx-cre-induced Met mutation, regeneration of the liver is impaired [19].
• To investigate a possible role for HGF/SF and its receptor, the Met tyrosine kinase, in embryonic development, we have analyzed their expression in mouse embryos from day 7.5 of gestation by whole-mount in situ hybridization [35].
• This novel noninvasive molecular imaging technique may be applied for the in vivo diagnosis, prognosis, and therapy of Met-expressing tumors [36].
• Data from cell culture and in vivo experiments implicate both FGFs and HGF as critical regulators of these processes [37].
• By RT-PCR analysis, Western blotting, and immunocytochemistry, we provide evidence for a high level of c-Met expression in GN11, but not in GT1-7, cells [38].

References