PMID- 10688652
OWN - NLM
STAT- MEDLINE
DCOM- 20000323
LR  - 20210526
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 20
IP  - 6
DP  - 2000 Mar
TI  - Disassociation of met-mediated biological responses in vivo: the natural 
      hepatocyte growth factor/scatter factor splice variant NK2 antagonizes growth but 
      facilitates metastasis.
PG  - 2055-65
AB  - Hepatocyte growth factor/scatter factor (HGF/SF) stimulates numerous cellular 
      activities capable of contributing to the metastatic phenotype, including growth, 
      motility, invasiveness, and morphogenetic transformation. When inappropriately 
      expressed in vivo, an HGF/SF transgene induces numerous hyperplastic and 
      neoplastic lesions. NK1 and NK2 are natural splice variants of HGF/SF; all 
      interact with a common receptor, Met. Although both agonistic and antagonistic 
      properties have been ascribed to each isoform in vitro, NK1 retains the full 
      spectrum of HGF/SF-like activities when expressed as a transgene in vivo. Here we 
      report that transgenic mice broadly expressing NK2 exhibit none of the phenotypes 
      characteristic of HGF/SF or NK1 transgenic mice. Instead, when coexpressed in 
      NK2-HGF/SF bitransgenic mice, NK2 antagonizes the pathological consequences of 
      HGF/SF and discourages the subcutaneous growth of transplanted Met-containing 
      melanoma cells. Remarkably, the metastatic efficiency of these same melanoma 
      cells is dramatically enhanced in NK2 transgenic host mice relative to wild-type 
      recipients, rivaling levels achieved in HGF/SF and NK1 transgenic hosts. 
      Considered in conjunction with reports that in vitro NK2 induces scatter, but not 
      other activities, these data strongly suggest that cellular motility is a 
      critical determinant of metastasis. Moreover, our results demonstrate how 
      alternatively structured ligands can be exploited in vivo to functionally 
      dissociate Met-mediated activities and their downstream pathways.
FAU - Otsuka, T
AU  - Otsuka T
AD  - Laboratories of Molecular Biology, National Cancer Institute, National Institutes 
      of Health, Bethesda, Maryland 20892, USA.
FAU - Jakubczak, J
AU  - Jakubczak J
FAU - Vieira, W
AU  - Vieira W
FAU - Bottaro, D P
AU  - Bottaro DP
FAU - Breckenridge, D
AU  - Breckenridge D
FAU - Larochelle, W J
AU  - Larochelle WJ
FAU - Merlino, G
AU  - Merlino G
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Protein Isoforms)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
SB  - IM
MH  - Animals
MH  - Cell Division
MH  - *Gene Expression Regulation, Neoplastic
MH  - Hepatocyte Growth Factor/*genetics
MH  - Liver/*pathology/*physiology
MH  - Liver Neoplasms, Experimental/*genetics/*pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Neoplasm Metastasis
MH  - Protein Isoforms/genetics
MH  - RNA Splicing
PMC - PMC110822
EDAT- 2000/02/25 09:00
MHDA- 2000/03/25 09:00
PMCR- 2000/03/01
CRDT- 2000/02/25 09:00
PHST- 2000/02/25 09:00 [pubmed]
PHST- 2000/03/25 09:00 [medline]
PHST- 2000/02/25 09:00 [entrez]
PHST- 2000/03/01 00:00 [pmc-release]
AID - 1657 [pii]
AID - 10.1128/MCB.20.6.2055-2065.2000 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2000 Mar;20(6):2055-65. doi: 10.1128/MCB.20.6.2055-2065.2000.