Figure 1

Schematic representation of the Met receptor and therapeutic strategies currently being developed to inhibit HGF-dependent Met activation and signaling in cancer. The Met receptor has an extracellular α-chain that binds HGF and a transmembrane β-chain that contains the tyrosine kinase domain and autophosphorylation sites that are essential for interacting with substrates. Activation of Met by HGF leads to receptor dimerization and recruitment of adaptor (GAB1, Grb2, Shc) and signaling (Ras/MAPK, PI3K/Akt, Src, STAT, Shp2) proteins. Downstream signaling promotes cell proliferation, altered cytoskeletal function, decreased cellular adhesion, increased cellular invasion, decreased apoptosis and enhanced DNA transcription. Anti-HGF approaches to inhibit Met signaling include anti-HGF antibodies that neutralize HGF and antagonists that block HGF binding to the Met receptor. A second approach includes the use of anti-Met antibodies that prevent HGF binding to Met or Met dimerization. Another approach is the use of specific Met tyrosine kinase inhibitors that prevent receptor second messenger signaling. Tocotrienols have also been found to be potent inhibitors of Met activation and signaling, but the exact mechanism mediating these effects are not completely understood at present. Targeting aberrant Met signaling in cancer cells can inhibit of downstream signaling pathways involved with tumor cell proliferation, motility, viability, morphology and epithelial-to-mesenchymal transition.