Disease relevance of SLTM

• We studied the protein expression of several components of the HGF/Met pathway on a cohort of 330 node-negative breast carcinomas using a tissue microarray annotated with 30-year, disease-specific patient follow-up data [1].
• Intriguingly, antibodies against the intracellular but not the extracellular domain of Met were prognostic, suggesting that overexpression of the cytoplasmic-tail of Met, perhaps through cleavage or truncating mutation, may play an important role in breast cancer progression [1].
• Interaction of the hepatocyte growth factor (HGF) with its receptor, the Met tyrosine kinase, results in invasive growth, a genetic program essential to embryonic development and implicated in tumor metastasis [2].
• After two to three passages, Met was downregulated in 37% of NFH-OSE cultures but persisted in 100% of FH-OSE cultures and ovarian cancer lines, like other epithelial differentiation markers that are stabilized in FH-OSE and neoplasia [3].
• In the last 10 years, evidence has accumulated that overexpression of Met protein is a distinguishing feature of almost every case of well-differentiated papillary carcinoma [4].

High impact information on SLTM

• In a colon carcinoma cell line (LoVo), the precursor is not cleaved and the Met protein is exposed at the cell surface as a single-chain polypeptide of 190 kDa (p190NC) [5].
• Numerous studies have demonstrated that overexpression of Met, the hepatocyte growth factor(HGF) receptor, plays an important role in tumorigenesis [1].
• All of the five NPC cell lines tested did not express hgf mRNA but expressed met mRNA, and tyrosine phosphorylation of Met protein was mainly induced by exogenous HGF stimulation in these cells [6].
• Compared with NPC, the Met expression level was higher in columnar nasopharyngeal epithelium but lower in squamous nasopharyngeal epithelium [6].
• Serine/threonine kinase Mirk/Dyrk1B is an inhibitor of epithelial cell migration and is negatively regulated by the Met adaptor Ran-binding protein M [7].

Biological context of SLTM

• Hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase Met are key regulators of epithelial motility and morphogenesis [8].
• Thus, unlike other genes, in which alternative splicing often gives rise to proteins with distinct activities, exon-skipping of MET exon 2 is predicted to decrease the abundance of a Met mRNA encoding a functional Met receptor [9].
• The tissue distribution of the Met/HGF receptor indicates that this molecule is involved in growth control of epithelial cells other than hepatocytes and suggests that its increased expression may confer a growth advantage to neoplastic cells [10].
• Immunostaining for Met protein was particularly intense in some cells located at the tumour periphery which were characterized by an invasive phenotype [11].
• Increased expression of Met protein is associated with up-regulation of hypoxia inducible factor-1 (HIF-1) in tumour cells in papillary carcinoma of the thyroid [11].

Anatomical context of SLTM

• c-Cbl is involved in Met signaling in B cells and mediates hepatocyte growth factor-induced receptor ubiquitination [8].
• In thyroid carcinomas of a specific histiotype the amount of Met protein, almost undetectable in the normal counterpart, was found to be increased more than 100-fold [10].
• Normal or increased levels of MET mRNA and Met protein were consistently found in fresh samples of carcinomas as well as in epithelial tumor cell lines [10].
• These studies suggest that HGF has an important role in placental trophoblast invasion through the activation of Met and the subsequent induction of 92-kDa collagenase in these cells [12].
• We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested [13].

Associations of SLTM with chemical compounds

• No mutation was found in the tyrosine kinase and the juxtamembrane domains of Met receptor in the five NPC cell lines tested [6].
• The only peptide bonds cleaved were the Gly3-Phe4 bond in methionine enkephalin, Gly4-Gly5 bond in Met-peptide, Gly3-Gly4 in His-peptide, and Gly3-Gly4 and Gly9-Gly10 bonds in HisMet-peptide [14].
• RT-PCR and immunoblot analyses demonstrated that low-oxygen tension (1% O2) stimulated the expression of Met mRNA and protein, respectively [15].
• Osteopontin-induced, integrin-dependent migration of human mammary epithelial cells involves activation of the hepatocyte growth factor receptor (Met) [16].
• In addition, the observed constitutive activation of Met was sustained under anchorage-independent conditions, and correlated with phosphatidyl inositol 3-kinase-dependent cell survival [17].

Analytical, diagnostic and therapeutic context of SLTM

• Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer [1].
• Western blot analysis has shown that the levels of the Met protein generally correspond to those of the mRNA [10].
• Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies [18].
• Dysregulation of MET causes marked accumulation of Met protein in tumour cells that is promptly detected by immunohistochemistry [4].
• The human first trimester trophoblast cell line (ED27) used in subsequent invasion studies was found to express c-met messenger ribonucleic acid by RT-PCR and Met protein by Western analysis, and underwent phosphorylation of tyrosine residues on Met with HGF exposure [12].

References