PMID- 1334458
OWN - NLM
STAT- MEDLINE
DCOM- 19930121
LR  - 20220511
IS  - 0261-4189 (Print)
IS  - 1460-2075 (Electronic)
IS  - 0261-4189 (Linking)
VI  - 11
IP  - 13
DP  - 1992 Dec
TI  - Extracellular proteolytic cleavage by urokinase is required for activation of 
      hepatocyte growth factor/scatter factor.
PG  - 4825-33
AB  - The extracellular protease urokinase is known to be crucially involved in 
      morphogenesis, tissue repair and tumor invasion by mediating matrix degradation 
      and cell migration. Hepatocyte growth factor/scatter factor (HGF/SF) is a 
      secretory product of stromal fibroblasts, sharing structural motifs with enzymes 
      of the blood clotting cascade, including a zymogen cleavage site. HGF/SF promotes 
      motility, invasion and growth of epithelial and endothelial cells. Here we show 
      that HGF/SF is secreted as a single-chain biologically inactive precursor 
      (pro-HGF/SF), mostly found in a matrix-associated form. Maturation of the 
      precursor into the active alpha beta heterodimer takes place in the extracellular 
      environment and results from a serum-dependent proteolytic cleavage. In vitro, 
      pro-HGF/SF was cleaved at a single site by nanomolar concentrations of pure 
      urokinase, generating the active mature HGF/SF heterodimer. This cleavage was 
      prevented by specific urokinase inhibitors, such as plasminogen activator 
      inhibitor type-1 and protease nexin-1, and by antibodies directed against the 
      urokinase catalytic domain. Addition of these inhibitors to HGF/SF responsive 
      cells prevented activation of the HGF/SF precursor. These data show that 
      urokinase acts as a pro-HGF/SF convertase, and suggest that some of the growth 
      and invasive cellular responses mediated by this enzyme may involve activation of 
      HGF/SF.
FAU - Naldini, L
AU  - Naldini L
AD  - Department of Biomedical Sciences and Oncology, University of Torino, Italy.
FAU - Tamagnone, L
AU  - Tamagnone L
FAU - Vigna, E
AU  - Vigna E
FAU - Sachs, M
AU  - Sachs M
FAU - Hartmann, G
AU  - Hartmann G
FAU - Birchmeier, W
AU  - Birchmeier W
FAU - Daikuhara, Y
AU  - Daikuhara Y
FAU - Tsubouchi, H
AU  - Tsubouchi H
FAU - Blasi, F
AU  - Blasi F
FAU - Comoglio, P M
AU  - Comoglio PM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Serine Proteinase Inhibitors)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Extracellular Matrix/drug effects/metabolism
MH  - Hepatocyte Growth Factor/*metabolism
MH  - Humans
MH  - Hydrolysis
MH  - Protein Processing, Post-Translational
MH  - Protein-Tyrosine Kinases/metabolism
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-met
MH  - Receptors, Cell Surface/metabolism
MH  - Serine Proteinase Inhibitors/pharmacology
MH  - Tumor Cells, Cultured
MH  - Urokinase-Type Plasminogen Activator/antagonists & inhibitors/*metabolism
PMC - PMC556958
EDAT- 1992/12/01 00:00
MHDA- 1992/12/01 00:01
PMCR- 1993/12/01
CRDT- 1992/12/01 00:00
PHST- 1992/12/01 00:00 [pubmed]
PHST- 1992/12/01 00:01 [medline]
PHST- 1992/12/01 00:00 [entrez]
PHST- 1993/12/01 00:00 [pmc-release]
AID - 10.1002/j.1460-2075.1992.tb05588.x [doi]
PST - ppublish
SO  - EMBO J. 1992 Dec;11(13):4825-33. doi: 10.1002/j.1460-2075.1992.tb05588.x.