Haploinsufficiency of c-Met in cd44-/- mice identifies a collaboration of CD44 and c-Met in vivo.
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.
Matzke
Alexandra
A
Forschungszentrum Karlsruhe, Institute for Toxicology and Genetics, Postfach 3640, 76021 Karlsruhe, Germany.
Sargsyan
Vardanush
V
Holtmann
Bettina
B
Aramuni
Gayane
G
Asan
Esther
E
Sendtner
Michael
M
Pace
Giuseppina
G
Howells
Norma
N
Zhang
Weiqi
W
Ponta
Helmut
H
Orian-Rousseau
Véronique
V
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
D018960:Hyaluronan Receptors; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met