PMID- 7765452
OWN - NLM
STAT- MEDLINE
DCOM- 19941207
LR  - 20211203
IS  - 0168-1656 (Print)
IS  - 0168-1656 (Linking)
VI  - 37
IP  - 2
DP  - 1994 Sep 30
TI  - Identification of functional domains in the hepatocyte growth factor and its 
      receptor by molecular engineering.
PG  - 109-22
AB  - Hepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding polypeptide 
      which shares structural domains with enzymes of the blood clotting cascade. 
      HGF/SF is secreted by cells of mesodermal origin and has powerful mitogenic, 
      motogenic and morphogenic activity on epithelial and endothelial cells. HGF/SF is 
      produced as a biologically inactive single-chain precursor (pro-HGF/SF) most of 
      which is sequestered on the cell surface or bound to the extracellular matrix. 
      Maturation into the active alpha beta heterodimer results from proteolytic 
      cleavage by a urokinase-type protease, which acts as a pro-HGF/SF convertase. The 
      primary determinant for receptor binding appears to be located within the 
      alpha-chain. The interaction of the alpha-chain with the receptor is sufficient 
      for the activation of the signal cascade involved in the motility response. 
      However, the complete HGF/SF protein seems to be required to elicit a mitogenic 
      response. HGF/SF binds with high affinity to a transmembrane receptor, p190MET, 
      encoded by the MET proto-oncogene. p190MET is the prototype of a distinct 
      subfamily of heterodimeric tyrosine kinases, including the putative receptors Ron 
      and Sea. The mature form of p190MET is a heterodimer of two disulfide-linked 
      subunits (alpha and beta). The alpha-subunit is extracellular and heavily 
      glycosylated. The beta-subunit consists of an extracellular portion involved in 
      ligand binding, a membrane spanning segment, and a cytoplasmic tyrosine kinase 
      domain. Both subunits derive from glycosylation and proteolytic cleavage of a 
      common precursor of 170 kDa. In polarized epithelial cells the HGF/SF receptor is 
      selectively exposed in the basolateral plasmalemma, where it is associated with 
      detergent-insoluble components. Two Met isoforms, carrying an intact ligand 
      binding domain but lacking the kinase domain due to truncation of the 
      beta-subunit, arise from alternative post-transcriptional processing of the 
      mature form. One truncated form is soluble and released from the cells. HGF/SF 
      binding triggers tyrosine autophosphorylation of the receptor beta-subunit. 
      Autophosphorylation on the major phosphorylation site Y1235 upregulates the 
      kinase activity of the receptor, increasing the Vmax of the phosphotransfer 
      reaction. Negative regulation of the kinase activity occurs through 
      phosphorylation of a unique serine residue (S985) located in the juxtamembrane 
      domain of the receptor. This phosphorylation is triggered by two distinct 
      pathways involving either protein kinase C activation or increase in 
      intracellular Ca2+ concentration. Upon ligand binding, the HGF/SF receptor 
      recruits and activates several cytoplasmic effectors, including 
      phosphatidylinositol 3-kinase (PI 3-K), phospholipase C-gamma (PLC-gamma), 
      pp60c-Src, a tyrosine phosphatase, and a Ras-guanine nucleotide 
      exchanger.(ABSTRACT TRUNCATED AT 400 WORDS)
FAU - Bardelli, A
AU  - Bardelli A
AD  - Department of Biomedical Sciences & Oncology, University of Torino School of 
      Medicine, Italy.
FAU - Ponzetto, C
AU  - Ponzetto C
FAU - Comoglio, P M
AU  - Comoglio PM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - Netherlands
TA  - J Biotechnol
JT  - Journal of biotechnology
JID - 8411927
RN  - 0 (MAS1 protein, human)
RN  - 0 (Proto-Oncogene Mas)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
GS  - MET
MH  - Amino Acid Sequence
MH  - Binding Sites/genetics
MH  - Biotechnology
MH  - Hepatocyte Growth Factor/*chemistry/genetics/metabolism
MH  - Humans
MH  - Molecular Sequence Data
MH  - Molecular Structure
MH  - Protein Engineering
MH  - Proto-Oncogene Mas
MH  - Proto-Oncogene Proteins c-met
MH  - Proto-Oncogenes
MH  - Receptor Protein-Tyrosine Kinases/*chemistry/genetics/metabolism
MH  - Signal Transduction
RF  - 86
EDAT- 1994/09/30 00:00
MHDA- 1994/09/30 00:01
CRDT- 1994/09/30 00:00
PHST- 1994/09/30 00:00 [pubmed]
PHST- 1994/09/30 00:01 [medline]
PHST- 1994/09/30 00:00 [entrez]
AID - 0168-1656(94)90002-7 [pii]
AID - 10.1016/0168-1656(94)90002-7 [doi]
PST - ppublish
SO  - J Biotechnol. 1994 Sep 30;37(2):109-22. doi: 10.1016/0168-1656(94)90002-7.