The binding of active HGF to the Met receptor induces activation of Met tyrosine kinase and the autophosphorylation of tyrosine residues in Met. Activation of c-Met by HGF leads to a variety of cellular signals that mediate tumor growth, metastasis, and angiogenesis. Binding of HGF to c-Met induces phosphorylation of C-terminally clustered tyrosine residues of tyrosine kinase, which results in biological activities in a wide variety of cells, including mitogenic, motogenic and morphogenic activities. HGF/Met signaling activates multiple signal transduction pathways, including the Src/focal adhesion kinase (FAK) pathway, the p120/signal transducer and activator of transcription (STAT) 3 pathway, the phosphoinositide-3 kinase (PI3K)/Akt pathway, and the Ras/MEK pathway.(figure 1)
Although the intracellular signaling pathways leading to specific or preferential activation of each biological response driven by HGF-Met receptor coupling have yet to be fully defined, preferential activation of signaling molecules and induction of gene expression responsible for activation of specific cellular responses are evident. Phosphotyrosine-dependent recruitment of the Grb-2/SOS complex activates Ras and subsequent phosphorylation events, including extracellular signal-regulated kinase. Activation of the Ras-ERK pathway is required for cellular proliferation. On the ather hand, the association and tyrosine phosphorylation of Gab-1, a docking protein that couples the MET receptor with multiple signaling proteins such as PI-3 kinase, PLC-γ, Shp-2 and Crk-2, plays a definite role in HGF-induces morphogenesis and cellular movement. HGF induces tyrosine phosphorylation of focal adhesion kinase andβ-catenin, threby enhancing the cell-ECM interaction and decreasing cadherin-mediated cell-cell adhesion. In addition, to transphosphrylation-dependent signaling pathways, the induction of gene expression of proteins involved in cell-associated proteolytic break-down of ECM components plays animportant role in branching tubulogenesis,including uPA, uPA receptor and membrane-type 1 matrix metalloprotease. In terms of anti-apoptosis, the activation of PI-3 kinase and downstream Akt and the induction of Bcl/Bcl-xL are likely pathways responsible for protection of cells from apoptosis by HGF. (Information from: Kunio Matsumoto and Toshikazu Nakamura,2001)
figure1: HGF signaling / pathway (Photocredit:Toshikazu NAKAMURA, et.al,2010)
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