title: c-Met recruits ICAM-1 as a coreceptor to compensate for the loss of CD44 in Cd44 null mice.
abstract: CD44 isoforms act as coreceptors for the receptor tyrosine kinases c-Met and VEGFR-2. However, Cd44 knockout mice do not show overt phenotypes, in contrast to Met and Vegfr-2 knockout mice. We hypothesized that CD44 is being compensated for by another factor in Cd44 null mice. Using RNAi technology and blocking experiments with antibodies, peptides, and purified ectodomains, as well as overexpression studies, we identified intercellular adhesion molecule-1 (ICAM-1) as a new coreceptor for c-Met in CD44-negative tumor cells and in primary hepatocytes obtained from Cd44 null mice. Most strikingly, after partial hepatectomy, CD44v6-specific antibodies inhibited liver cell proliferation and c-Met activation in wild-type mice, whereas ICAM-1-specific antibodies interfered with liver cell proliferation and c-Met activation in Cd44 knockout mice. These data show that ICAM-1 compensates for CD44v6 as a coreceptor for c-Met in Cd44 null mice. Compensation of proteins by members of the same family has been widely proposed to explain the lack of phenotype of several knockout mice. Our experiments demonstrate the functional substitution of a protein by a heterologous one in a knockout mouse.
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
authors.forename: Vivienne
authors.initials: V
authors.lastname: Olaku
authors.forename: Alexandra
authors.initials: A
authors.lastname: Matzke
authors.forename: Claudia
authors.initials: C
authors.lastname: Mitchell
authors.forename: Susanne
authors.initials: S
authors.lastname: Hasenauer
authors.forename: Arul
authors.initials: A
authors.lastname: Sakkaravarthi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Pace
authors.forename: Helmut
authors.initials: H
authors.lastname: Ponta
authors.forename: Véronique
authors.initials: V
authors.lastname: Orian-Rousseau
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D005816:Genetic Complementation Test; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D018799:Intercellular Adhesion Molecule-1; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2