RGD Reference Report - Disassociation of met-mediated biological responses in vivo: the natural hepatocyte growth factor/scatter factor splice variant NK2 antagonizes growth but facilitates metastasis. - Rat Genome Database

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Disassociation of met-mediated biological responses in vivo: the natural hepatocyte growth factor/scatter factor splice variant NK2 antagonizes growth but facilitates metastasis.

Authors: Otsuka, T  Jakubczak, J  Vieira, W  Bottaro, DP  Breckenridge, D  LaRochelle, WJ  Merlino, G 
Citation: Otsuka T, etal., Mol Cell Biol. 2000 Mar;20(6):2055-65.
RGD ID: 8548538
Pubmed: PMID:10688652   (View Abstract at PubMed)
PMCID: PMC110822   (View Article at PubMed Central)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Neoplasm Metastasis  IDA 8548538associated with MelanomaRGD 
Neoplasm Metastasis  ISOHGF (Homo sapiens)8548538; 8548538associated with MelanomaRGD 

Objects Annotated

Genes (Rattus norvegicus)
Hgf  (hepatocyte growth factor)

Genes (Mus musculus)
Hgf  (hepatocyte growth factor)

Genes (Homo sapiens)
HGF  (hepatocyte growth factor)


Additional Information