Is a proto-oncogene that encodes a protein known as a receptor hepatocyte growth factor (HGFR) is (modified genes MNNG HOS or MET) of C-Met. The hepatocyte growth factor receptor protein tyrosine kinases, activity.The primary single chain precursor protein is cleaved to produce are connected so as to form a receptor disulfide and mature post-translationally and α and β-subunit are. MET is a membrane receptor is essential for wound healing and embryonic development. Hepatocyte growth factor (HGF) is a ligand known only MET receptor. Expression of HGF while being limited to cells of mesenchymal origin, usually, MET is expressed by cells of epithelial origin. During stimulation HGF, MET induced biological effects of some leading to the program known as invasive growth together.
Abnormal activation of MET in cancer that you meet the growth of the tumor, the formation new blood vessels that provide a tumor and spread of the cancer and other organs nutrients (metastasis) of (newborn) results in active unusually I correlates with poor prognosis. MET has been deregulated human malignancies, including cancer kidney, liver, stomach, breast, brain, many kinds of. Typically, in order to reproduce the damaged tissue in adults or generate new tissue in the embryonic cells, it is possible to grow invasively, stem and progenitor cells only express met. However, it is believed that meets the cancer stem cells, and thus steal the ability of normal stem cells to express cause distribution elsewhere in the body and cancer resistance. Different mutations of the MET gene are associated with papillary renal cell carcinoma.
Result of phosphoric acid transition of 1235 and Tyr 1234 of tyrosine Tyr, MET activation, to induce MET kinase catalytic activity by its ligand HGF. Launching the full spectrum of the biological activity driven by MET, known as growth program invasive collectively thereby tyrosine These two sensors engage various signals. Sensor, phosphatidylinositol 3 GRB2, SHC, and SRC, – through GAB1 scaffolding protein, interacts with intracellular multi-substrate docking site of MET directly or indirectly, as a regulatory subunit P85 kinase (PI3K).
While participating in the recruitment of GRB2, in 1356 and Tyr 1349 Tyr of multi-substrate docking site, GAB1, SRC, and there is both involved in the interaction with the SHC, 1356 of Tyr only phospholipase Cγ (PLC -γ SHP2 and P85). Binds to MET and GAB1 key cellular response coordinator, met with intracellular region with high affinity, but is, GAB1 low dialogue affinity.Upon MET, tyrosine residues of more than one becomes phosphorylated, in turn, the PI3K In the appointment number of signaling effectors, including, PLC-γ and SHP2,. GAB1 of MET phosphorylation leads to mediate delayed signal for the majority of downstream signaling pathways.
MET is mediated complex programs known as invasive growth. Lead morphogenesis.During embryonic development, flat in the body of the dimension of the fetus, the conversion of two-layer disk, activation of MET mitosis number of epithelial phenotype in cells with the role behavior of spindle-shaped mesenchymal phenotype I rely on the conversion of Kano cell. This process is referred to as (EMT) epithelial-mesenchymal transition. Then, in embryonic development, gastrulation, angiogenesis, migration myoblasts, bone remodeling, and MET is essential for neuronal sprouting and others. For mouse MET who died during pregnancy due to a serious defect in the development of the placenta, MET is essential to embryonic development. Moreover, MET is required for critical processes such as wound healing and liver regeneration in adults.
So, is the ligand the only known for the formation of Met, the HGF HGF: the MET, MET the biological activity of complex block. For this purpose, uncleavable form of HGF HGF truncated, and anti-HGF neutralizing antibodies, have been used so far. The main limitation of HGF inhibitors is that they will block the HGF-dependent activation of MET only. As MET, because it conflicts with HGF without binding induces activation of the receptor, NK4 behaves as a full agonist. NK4 is a molecule having two regions kringle HGF 4 N-terminal and acute. Furthermore, NK4, there angiostatins similar in structure due to have anti-angiogenic activity. The neutralizing anti-HGF antibody, it was tested in combination first, different epitopes, three antibodies are necessary to prevent the activation of the MET tyrosine kinase least operating at HGF has been found. Recently, fully human monoclonal antibodies, which are separately connected, is currently available to be able to lead to tumor regression in murine models.Two anti-HGF antibody to neutralize human HGF has been shown: human fully human AMG102 and AV299.
Uncleavable HGF, which is designed in the form of pro-HGF and a single amino acid substitution that prevents the maturation of the molecule. By combining met with displacement mature HGF with high affinity, Integra HGF is able to block the biological response is MET-induced. In addition, it is a conflict with the wild-type pro-HGF endogenous for the catalytic domain of the protease cleavage HGF precursor an integrated HGF. Expression of local and systemic integrated HGF inhibits the growth of tumor, more importantly, can prevent metastasis.