Mutant Met-mediated transformation is ligand-dependent and can be inhibited by HGF antagonists

被引:111
作者
Michieli, P [1 ]
Basilico, C [1 ]
Pennacchietti, S [1 ]
Maffè, A [1 ]
Tamagnone, L [1 ]
Giordano, S [1 ]
Bardelli, A [1 ]
Comoglio, PM [1 ]
机构
[1] Univ Turin, Sch Med, IRCC, Inst Canc Res & Treatment,Dept Mol Oncol, I-10060 Turin, Italy
关键词
growth factors; invasive growth; oncogenes; transformation; tyrosine kinases;
D O I
10.1038/sj.onc.1202899
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutations in the genes encoding for Met, Ret and Kit receptor tyrosine kinases invariably result in increased kinase activity and in the acquisition of transforming potential. However, the requirement of receptor ligands for the transformation process is still unclear. We have investigated the role of hepatocyte growth factor (HGF), the high-affinity ligand for Met, in mutant Met-mediated cell transformation. We provide evidence that the transforming potential displayed by mutant forms of Met found in human cancer is not only sensitive but entirely dependent on the presence of HGF, by showing that mutant Met transforms NIH3T3 fibroblasts, which produce endogenous HGF, but is not able to transform epithelial cells, unless exogenous HGF is supplied. Accordingly, mutant Met-induced transformation of NIH3T3 cells can be inhibited by HGF antagonists and increased by HGF stimulation, We also show that an engineered Met receptor which contains an oncogenic mutation but is impaired in its ability to bind HGF completely loses its transforming activity, which can be rescued by causing receptor dimerization using a monoclonal antibody. These results indicate that point mutations resulting in Met kinase activation are necessary but not sufficient to cause cell transformation, the latter being dependent on ligand-induced receptor dimerization, They also suggest that mutant Met-driven tumour growth depends on the availability and tissue distribution of active HGF, and provide proof-of-concept for the treatment of mutant-Met related pathologies by HGF-antagonizing drugs.
引用
收藏
页码:5221 / 5231
页数:11
相关论文
共 71 条
[1]   A natural hepatocyte growth factor scatter factor autocrine loop in myoblast cells and the effect of the constitutive met kinase activation on myogenic differentiation [J].
Anastasi, S ;
Giordano, S ;
Sthandier, O ;
Gambarotta, G ;
Maione, R ;
Comoglio, P ;
Amati, P .
JOURNAL OF CELL BIOLOGY, 1997, 137 (05) :1057-1068
[2]   Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth [J].
Bardelli, A ;
Longati, P ;
Gramaglia, D ;
Basilico, C ;
Tamagnone, L ;
Giordano, S ;
Ballinari, D ;
Michieli, P ;
Comoglio, PM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (24) :14379-14383
[3]  
BARDELLI A, 1997, BIOCHIM BIOPHYS ACTA, V1333, P41
[4]  
Birchmeier W, 1997, CIBA F SYMP, V212, P230
[5]   ESSENTIAL ROLE FOR THE C-MET RECEPTOR IN THE MIGRATION OF MYOGENIC PRECURSOR CELLS INTO THE LIMB BUD [J].
BLADT, F ;
RIETHMACHER, D ;
ISENMANN, S ;
AGUZZI, A ;
BIRCHMEIER, C .
NATURE, 1995, 376 (6543) :768-771
[6]   Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation [J].
Bongarzone, I ;
Vigano, E ;
Alberti, L ;
Borrello, MG ;
Pasini, B ;
Greco, A ;
Mondellini, P ;
Smith, DP ;
Ponder, BAJ ;
Romeo, G ;
Pierotti, MA .
ONCOGENE, 1998, 16 (18) :2295-2301
[7]  
Borrello MG, 1995, ONCOGENE, V11, P2419
[8]   IDENTIFICATION OF THE HEPATOCYTE GROWTH-FACTOR RECEPTOR AS THE C-MET PROTOONCOGENE PRODUCT [J].
BOTTARO, DP ;
RUBIN, JS ;
FALETTO, DL ;
CHAN, AML ;
KMIECIK, TE ;
VANDEWOUDE, GF ;
AARONSON, SA .
SCIENCE, 1991, 251 (4995) :802-804
[9]   HEPATOCYTE GROWTH-FACTOR IS A POTENT ANGIOGENIC FACTOR WHICH STIMULATES ENDOTHELIAL-CELL MOTILITY AND GROWTH [J].
BUSSOLINO, F ;
DIRENZO, MF ;
ZICHE, M ;
BOCCHIETTO, E ;
OLIVERO, M ;
NALDINI, L ;
GAUDINO, G ;
TAMAGNONE, L ;
COFFER, A ;
COMOGLIO, PM .
JOURNAL OF CELL BIOLOGY, 1992, 119 (03) :629-641
[10]   Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease [J].
Carlomagno, F ;
Melillo, RM ;
Visconti, R ;
Salvatore, G ;
De Vita, G ;
Lupoli, G ;
Yu, YB ;
Jing, SQ ;
Vecchio, G ;
Fusco, A ;
Santoro, M .
ENDOCRINOLOGY, 1998, 139 (08) :3613-3619