Exp Mol Med.  2006 Oct;38(5):565-573.

An alternatively spliced form of Met receptor is tumorigenic

• Lee JH
• Gao CF
• Lee CC
• Kim MD
• Vande Woude GF

Abstract

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). Previously, one of the authors identified an alternatively spliced form of Met (Met-SM) that lacked a single exon of a 47-amino-acid segment in the juxtamembrane domain. Here we report that Met-SM is a potent transforming gene in NIH3T3 mouse fibroblast cells. Met-SM-transfected NIH3T3 cells show stronger foci-forming activity than wild type-Met-transfected ones. In addition, Met-SM-transfected NIH3T3 cells form colonies in soft agar and are tumorigenic in athymic nu/nu mice. Furthermore, HGF/SF significantly increases the focus-forming activity of Met-SM comparing to wild type Met. The amount of protein and of tyrosine kinase activity of Met-SM accumulates to a high level following HGF/SF treatment. The accumulation of Met-SM correlated well with its delayed ubiquitination and increased stability. These results are consistent with the important role of the juxtamembrane domain in protein stability of Met receptor and suggest that the alternatively-spliced form may contribute to the development and progression of human cancer.

Keyword

alternative splicing; hepatocyte growth factor; neoplasms; proto-oncogene proteins c-met

MeSH Terms

Proto-Oncogene Proteins c-met/*metabolism/*physiology
Protein Isoforms/metabolism/physiology
NIH 3T3 Cells
Mutant Proteins/metabolism/physiology
Mice, Nude
Mice
Hepatocyte Growth Factor/pharmacology
Female
Down-Regulation
Carcinogens/*metabolism
Carcinogenicity Tests
Animals
*Alternative Splicing