Evolutionary divergence of platelet-derived growth factor alpha receptor signaling mechanisms

T. Guy Hamilton, Richard A. Klinghoffer, Philip D. Corrin, Philippe Soriano

Research output: Contribution to journalArticlepeer-review

287 Scopus citations

Abstract

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 (PDGFαR) is fused to the cytosolic domain of Drosophila Torso (αTor) or the mouse fibroblast growth factor receptor 1 (αFR). αTor homozygous embryos exhibit significant rescue of neural crest and angiogenesis defects normally found in PDGFαR-null embryos yet fail to rescue skeletal or extraembryonic defects. This phenotype was associated with the ability of αTor to stimulate the mitogen-activated protein (MAP) kinase pathway to near wildtype levels but failure to completely activate other pathways, such as phosphatidylinositol (PI) 3-kinase. The αFR chimeric receptor fails to rescue any aspect of the PDGFαR-null phenotype. Instead, αFR expression leads to a gain-of-function phenotype highlighted by ectopic bone development. The αFR 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.

Original languageEnglish
Pages (from-to)4013-4025
Number of pages13
JournalMolecular and Cellular Biology
Volume23
Issue number11
DOIs
StatePublished - Jun 2003
Externally publishedYes

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