title: Haploinsufficiency of c-Met in cd44-/- mice identifies a collaboration of CD44 and c-Met in vivo.
abstract: Recent evidence has shown that the activation of receptor tyrosine kinases is not only dependent on binding of their ligands but in addition requires adhesion molecules as coreceptors. We have identified CD44v6 as a coreceptor for c-Met in several tumor and primary cells. The CD44v6 ectodomain is required for c-Met activation, whereas the cytoplasmic tail recruits ERM proteins and the cytoskeleton into a signalosome complex. Here we demonstrate that c-Met (and hepatocyte growth factor and Gab1) is haploinsufficient in a cd44-/- background, as the cd44-/-; met+/- (and cd44-/-; hgf+/- and cd44-/-; gab1+/-) mice die at birth. They have impaired synaptic transmission in the respiratory rhythm-generating network and alterations in the phrenic nerve. These results are the first genetic data showing that CD44 and c-Met collaborate in vivo and that they are involved in synaptogenesis and axon myelination in the central and peripheral nervous systems.
authors.affiliation: Forschungszentrum Karlsruhe, Institute for Toxicology and Genetics, Postfach 3640, 76021 Karlsruhe, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Matzke
authors.forename: Vardanush
authors.initials: V
authors.lastname: Sargsyan
authors.forename: Bettina
authors.initials: B
authors.lastname: Holtmann
authors.forename: Gayane
authors.initials: G
authors.lastname: Aramuni
authors.forename: Esther
authors.initials: E
authors.lastname: Asan
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Pace
authors.forename: Norma
authors.initials: N
authors.lastname: Howells
authors.forename: Weiqi
authors.initials: W
authors.lastname: Zhang
authors.forename: Helmut
authors.initials: H
authors.lastname: Ponta
authors.forename: Véronique
authors.initials: V
authors.lastname: Orian-Rousseau
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D006238:Haploidy; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008168:Lung / Q000002:abnormalities / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000473:pathology; D009412:Nerve Fibers / Q000473:pathology; D010791:Phrenic Nerve / Q000473:pathology / Q000648:ultrastructure; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: D018960:Hyaluronan Receptors; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met