Evolutionary divergence of platelet-derived growth factor alpha receptor signaling mechanisms.
Receptor tyrosine kinases (RTKs) direct diverse cellular and developmental responses by stimulating a relatively small number of overlapping signaling pathways. Specificity may be determined by RTK expression patterns or by differential activation of individual signaling pathways. To address this issue we generated knock-in mice in which the extracellular domain of the mouse platelet-derived growth factor alpha receptor (PDGFalphaR) is fused to the cytosolic domain of Drosophila Torso (alpha(Tor)) or the mouse fibroblast growth factor receptor 1 (alpha(FR)). alpha(Tor) homozygous embryos exhibit significant rescue of neural crest and angiogenesis defects normally found in PDGFalphaR-null embryos yet fail to rescue skeletal or extraembryonic defects. This phenotype was associated with the ability of alpha(Tor) to stimulate the mitogen-activated protein (MAP) kinase pathway to near wild-type levels but failure to completely activate other pathways, such as phosphatidylinositol (PI) 3-kinase. The alpha(FR) chimeric receptor fails to rescue any aspect of the PDGFalphaR-null phenotype. Instead, alpha(FR) expression leads to a gain-of-function phenotype highlighted by ectopic bone development. The alpha(FR) phenotype was associated with a failure to limit MAP kinase signaling and to engage significant PI3-kinase response. These results suggest that precise regulation of divergent downstream signaling pathways is critical for specification of RTK function.
Program in Developmental Biology and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
T Guy
TG
Hamilton
Richard A
RA
Klinghoffer
Philip D
PD
Corrin
Philippe
P
Soriano
D000818:Animals; D001808:Blood Vessels / Q000033:anatomy & histology / Q000254:growth & development; D001842:Bone and Bones / Q000002:abnormalities / Q000502:physiology; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000033:anatomy & histology / Q000502:physiology*; D004625:Embryo, Nonmammalian; D019143:Evolution, Molecular; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D017930:Genes, Reporter; D051379:Mice; D008822:Mice, Transgenic; D009432:Neural Crest / Q000254:growth & development / Q000473:pathology; D010641:Phenotype; D010920:Placenta / Q000002:abnormalities; D010929:Placentation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D029721:Drosophila Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha; C080148:tor protein, Drosophila