Growth factors induce a variety of cellular responses including proliferation, survival and migration. A number of growth factors activate receptors with intrinsic tyrosine kinase activity. Extensive studies in cell culture systems have shown that receptor engagement leads to binding of intracellular effectors, and the activation of individual signaling pathways. However, the physiological relevance of utilizing one or another pathway remains mostly unknown. In this proposal, we will focus on identifying the roles of individual signaling pathways downstream of platelet derived growth factors (PDGFs), which are involved in developmental and physiological responses in many tissues, including the vasculature, the kidney, the skeleton and neural crest derivatives. We will achieve our goals by generating mutant mice that express PDGF receptors in which the individual docking sites for various effectors have been mutated. We will further concentrate our efforts on determining if signaling pathways between PDGF receptors and other growth factor receptors are redundant, using genetic substitution methods. To further investigate the role of PDGF signaling in development, we will make use of conditional gene ablation to test the role of PDGF signaling in specific tissues. These studies should help us understand growth factor regulatory mechanisms, and provide information on the specificity and interplay of growth factor signaling pathways in physiological processes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD025326-15
Application #
6875667
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Moody, Sally Ann
Project Start
1989-07-01
Project End
2006-01-17
Budget Start
2005-01-01
Budget End
2006-01-17
Support Year
15
Fiscal Year
2005
Total Cost
$435,851
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Zou, Hongyan; Feng, Rui; Huang, Yong et al. (2015) Double minute amplification of mutant PDGF receptor ? in a mouse glioma model. Sci Rep 5:8468
Lewis, Ace E; Hwa, Jennifer; Wang, Rong et al. (2015) Neural crest defects in ephrin-B2 mutant mice are non-autonomous and originate from defects in the vasculature. Dev Biol 406:186-95
Bush, Jeffrey O; Soriano, Philippe (2012) Eph/ephrin signaling: genetic, phosphoproteomic, and transcriptomic approaches. Semin Cell Dev Biol 23:26-34
Olson, Lorin E; Soriano, Philippe (2011) PDGFR? signaling regulates mural cell plasticity and inhibits fat development. Dev Cell 20:815-26
Bush, Jeffrey O; Soriano, Philippe (2010) Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries. Genes Dev 24:2068-80
Raymond, Christopher S; Soriano, Philippe (2010) ROSA26Flpo deleter mice promote efficient inversion of conditional gene traps in vivo. Genesis 48:603-6
Wassarman, Paul M; Soriano, Philippe M (2010) Guide to techniques in mouse development. Preface. Methods Enzymol 476:xix
Olson, Lorin E; Soriano, Philippe (2009) Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell 16:303-13
Bush, Jeffrey O; Soriano, Philippe (2009) Ephrin-B1 regulates axon guidance by reverse signaling through a PDZ-dependent mechanism. Genes Dev 23:1586-99
Qiu, Runxiang; Wang, Xiuyun; Davy, Alice et al. (2008) Regulation of neural progenitor cell state by ephrin-B. J Cell Biol 181:973-83

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