PMID- 9001234
OWN - NLM
STAT- MEDLINE
DCOM- 19970218
LR  - 20210526
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 17
IP  - 2
DP  - 1997 Feb
TI  - Degradation of the Met tyrosine kinase receptor by the ubiquitin-proteasome 
      pathway.
PG  - 799-808
AB  - The Met tyrosine kinase receptor is a widely expressed molecule which mediates 
      pleiotropic cellular responses following activation by its ligand, hepatocyte 
      growth factor/scatter factor (HGF/SF). In this communication we demonstrate that 
      significant Met degradation is induced by HGF/SF and that this degradation can be 
      blocked by lactacystin, an inhibitor of proteasome activity. We also show that 
      Met is rapidly polyubiquitinated in response to ligand and that polyubiquitinated 
      Met molecules, which are normally unstable, are stabilized by lactacystin. Both 
      HGF/SF-induced degradation and polyubiquitination of Met were shown to be 
      dependent on the receptor possessing intact tyrosine kinase activity. Finally, we 
      found that a normally highly labile 55-kDa fragment of the Met receptor is 
      stabilized by lactacystin and demonstrate that it represents a cell-associated 
      remnant that is generated following the ligand-independent proteolytic cleavage 
      of the Met receptor in its extracellular domain. This truncated Met molecule 
      encompasses the kinase domain of the receptor and is itself tyrosine 
      phosphorylated. We conclude that the ubiquitin-proteasome pathway plays a 
      significant role in the degradation of the Met tyrosine kinase receptor as 
      directed by ligand-dependent and -independent signals. We propose that this 
      proteolytic pathway may be important for averting cellular transformation by 
      desensitizing Met signaling following ligand stimulation and by eliminating 
      potentially oncogenic fragments generated via extracellular cleavage of the Met 
      receptor.
FAU - Jeffers, M
AU  - Jeffers M
AD  - ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, 
      Maryland 21702, USA.
FAU - Taylor, G A
AU  - Taylor GA
FAU - Weidner, K M
AU  - Weidner KM
FAU - Omura, S
AU  - Omura S
FAU - Vande Woude, G F
AU  - Vande Woude GF
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Cyclopentanes)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Ligands)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Peptide Fragments)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Ubiquitins)
RN  - 133343-34-7 (lactacystin)
RN  - 20350-15-6 (Brefeldin A)
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)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/analogs & derivatives/pharmacology
MH  - Animals
MH  - Brefeldin A
MH  - Cell Line
MH  - Cell Membrane/metabolism
MH  - Cyclopentanes/pharmacology
MH  - Cysteine Endopeptidases/*metabolism
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Hepatocyte Growth Factor/*pharmacology
MH  - Humans
MH  - Ligands
MH  - Molecular Weight
MH  - Multienzyme Complexes/*metabolism
MH  - Nerve Growth Factors/pharmacology
MH  - Peptide Fragments/chemistry/metabolism
MH  - Phosphorylation
MH  - Proteasome Endopeptidase Complex
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-met
MH  - Receptor Protein-Tyrosine Kinases/genetics/*metabolism
MH  - Recombinant Fusion Proteins
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - Transfection
MH  - Ubiquitins/*metabolism
PMC - PMC231806
EDAT- 1997/02/01 00:00
MHDA- 1997/02/01 00:01
PMCR- 1997/02/01
CRDT- 1997/02/01 00:00
PHST- 1997/02/01 00:00 [pubmed]
PHST- 1997/02/01 00:01 [medline]
PHST- 1997/02/01 00:00 [entrez]
PHST- 1997/02/01 00:00 [pmc-release]
AID - 10.1128/MCB.17.2.799 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1997 Feb;17(2):799-808. doi: 10.1128/MCB.17.2.799.