Coupling Met to specific pathways results in distinct developmental outcomes.
Receptor tyrosine kinases (RTKs) mediate distinct biological responses by stimulating similar intracellular signaling pathways. Whether the specificity of the response is determined by qualitative or quantitative differences in signaling output is not known. We addressed this question in vivo by replacing the multifunctional docking sites of Met, the receptor for hepatocyte growth factor, with specific binding motifs for phosphatidylinositol-3 kinase, Src tyrosine kinase, or Grb2 (Met(2P), Met(2S), and Met(2G), respectively). All three mutants retained normal signaling through the multiadaptor Gab1, but differentially recruited specific effectors. While Met(2G) mice developed normally, Met(2P) and Met(2S) mice were loss-of-function mutants displaying different phenotypes and rescue of distinct tissues. These data indicate that RTK-mediated activation of specific signaling pathways is required to fulfill cell-specific functions in vivo.
Maina
F
F
European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117, Heidelberg, Germany. maina@ibdm.univ-mrs.fr
Panté
G
G
Helmbacher
F
F
Andres
R
R
Porthin
A
A
Davies
A M
AM
Ponzetto
C
C
Klein
R
R
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001369:Axons / Q000502:physiology; D001665:Binding Sites / Q000235:genetics; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005333:Fetus / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000196:embryology; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology; D016254:Mutagenesis, Insertional; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D010929:Placentation; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D019859:Proto-Oncogene Proteins c-met; D014443:Tyrosine; D019061:src-Family Kinases; C490897:Gab1 protein, mouse