This cell surface receptor is expressed in epithelial cells of numerous organs, such as the liver, pancreas, prostate, kidney, muscle and bone marrow, throughout both embryo genesis and adulthood.
(-)-MK 801 Maleate The Sema domain shares sequence homology with domains found in the semaphorin and plexin fam ilies. The PSI domain follows the Sema domain, A 205804 spans approximately 50 residues and includes four disulphide bonds. This domain is connected to the transmembrane helix via four immunoglob ulin?plexin?transcription domains, which are related to immunoglobulin like domains and are found in integrins, plexins and transcription factors. Intracellularly, the c MET receptor con tains a tyrosine kinase catalytic domain flanked by distinctive juxtamembrane and carboxy terminal sequences. The ligand for c MET was identified by two independent studies as both a motility factor and a scatter factor for hepatocytes, and this factor was later found to be the same molecule: HGF, also known as scatter factor.
Physiologically, c MET is A 205804 responsible for the cell scattering phenotype, as first demonstrated with MDCK cells treated with HGF. This process involves the disruption of cadherin based cell?cell contacts and subsequent cell motility, and is a key epithelial function in embryogenesis and wound repair. During embryogenesis, this motility func tion of c MET is crucial for the long range migration of skeletal muscle progenitor cells. Ablation of the MET or Hgf gene in mice results in the complete absence of all muscle groups derived from these cells. During development, c MET and HGF provide essential signals for survival and proliferation of hepatocytes and placental trophoblast cells, con sequently, MET or Hgf knockout embryos show markedly reduced liver size.
As well, altered pla cental development in Hgf and MET knockout mice is responsible for the death (-)-MK 801 Maleate of these animals in utero. The complex phenotype that results from c MET signaling involves a number of molecular events, which have been described in detail in previous reviews. HGF binding to c MET results in receptor homodimerization and phosphorylation of two tyrosine residues located within the catalytic loop of the tyrosine kinase domain. Subsequently, tyrosines 1349 and 1356 in the carboxy terminal tail become phosphory lated. These two tyrosines form a tandem SH2 recognition motif unique to c MET.
When these A 205804 tyrosines become phosphory lated, they recruit signaling effectors that include the adaptor proteins Growth factor receptor bound protein 2, Src homology 2 containing and v crk sarcoma virus CT10 oncogene homolog and CRK like, the effec tor molecules phosphatidylinositol 3 kinase, phospholipase Cg and v src sar coma viral oncogene homolog, Src homol ogy domain containing 5 inositol phosphatase and the transcription factor signal transducer and activator of transcrip tion.
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