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Molecular and Cellular Biology, June 2003, p. 4013-4025, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.4013-4025.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Evolutionary Divergence of Platelet-Derived Growth Factor Alpha Receptor Signaling Mechanisms

T. Guy Hamilton, Richard A. Klinghoffer,{dagger} Philip D. Corrin, and Philippe Soriano*

Program in Developmental Biology and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109

Received 18 November 2002/ Returned for modification 13 January 2003/ Accepted 17 March 2003

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 (PDGF{alpha}R) 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 PDGF{alpha}R-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 PDGF{alpha}R-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.

* Corresponding author. Mailing address: Program in Developmental Biology and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109. Phone: (206) 667-6825. Fax: (206) 667-6522. E-mail: psoriano{at}fhcrc.org.

{dagger} Present address: Ceptyr Inc., Bothell, WA 98021.

Molecular and Cellular Biology, June 2003, p. 4013-4025, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.4013-4025.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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