Open AccessInhibitory effect of c‐Met mutants on the formation of branching tubules by a porcine aortic endothelial cell line
Author(s) -
Maemura Marino,
Yoshimoto Akira,
Tsukada Yuichi,
Morishita Yasuyuki,
Miyazawa Keiji,
Tanaka Toshiaki,
Kitamura Naomi
Publication year - 2006
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2006.00335.x
Subject(s) - hepatocyte growth factor , mutant , microbiology and biotechnology , point mutation , mapk/erk pathway , extracellular , kinase , biology , cell culture , cell , chemistry , receptor , biochemistry , gene , genetics
The association of hepatocyte growth factor (HGF) with its high‐affinity receptor (c‐Met) has been shown to induce mitogenesis, motogenesis and morphogenesis in a variety of cell types. Various point mutations in c‐Met have been identified in hereditary and sporadic papillary renal carcinomas as well as in other carcinomas. In the present study, we examined the effects of c‐Met point mutations on the morphology of a porcine aortic endothelial (PAE) cell line. When cultured in three‐dimensional collagen gel, PAE cells formed branching tubule structures, and HGF treatment caused breakdown of the structures and induced a scattered morphology. The exogenous expression of c‐Met point mutants inhibited the formation of tubules. HGF treatment induced the formation of tubules by PAE cells expressing some c‐Met mutants, but it induced the scattering of PAE cells expressing other c‐Met mutants. The presence of a low concentration of a mitogen‐activated protein kinase/extracellular signal‐regulated kinase kinase (MEK) inhibitor cancelled the inhibitory effect of the c‐Met point mutations on the formation of tubules. These results suggest that c‐Met point mutations affect the extracellular signal‐regulated kinase (ERK) signaling required for the formation of tubules by PAE cells, and HGF binding changes the conformation of c‐Met mutants, leading to the different signals required for formation of tubules and cell scattering. ( Cancer Sci 2006; 97: 1343–1350)