This application represents the third competitive renewal for this research program. Orginating from our interesting in the zinc finger tumor suppressor protein WT1, we identified the Sproutyl gene as a WT1 target gene relevant to kidney differentiation and the regulation of cellular growth. Over the past four years we confirmed this idea through the creation of a Spryl knockout mouse that exhibited a severe renal phenotype. We also showed that Sproutyl and other Sprouty proteins interefered with signaling through RTKs at the level of ras activation. Nevertheless many questions remain in the field including the role of the other sprouty proteins in animal devlopment; the exact point of action and mechanism of the sprouty proteins in inhibting signal transduction and the critical partner proteins for sprouty action. We believe that the four sprouty genes in higher eukaryotes play distinct roles in development and work through some common and some distinct mechamisms. Lastly emerging data suggest that the Sprouty genes may be bonafide tumor suppressors. Hence in the next funding period we propose a number of biochemical as well as animal model approaches towards the fuller understanding of the sprouty family of proteins. Specifically we will 1. Determine the point of action of the sprouty proteins in signal transduction through the Ras/MAP kinase and other pathways through the use of knockout cells and repeletion with wild-type and mutant forms of Sprouty proteins 2. Determine the identity of the critical partner proteins of Sprouty which interact in a phosphorylation dependent and independent manner to modulate signal transduction 3. Determine the role of Sproutyl as a tumor suppressor protein in an animal model of breast cancer 4. Characterize the biochemical function of the Sprouty 3 protein and target the Spn/3 gene in mice to determine the role of this protein in signal transduction and animal development.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Yassin, Rihab R,
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Nabet, Behnam; Ó Broin, Pilib; Reyes, Jaime M et al. (2015) Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape. Cell Rep 12:1300-13
Kuracha, Murali R; Siefker, Ed; Licht, Jonathan D et al. (2013) Spry1 and Spry2 are necessary for eyelid closure. Dev Biol 383:227-38
Hwangpo, Tracy Anh; Jordan, J Dedrick; Premsrirut, Prem K et al. (2012) G Protein-regulated inducer of neurite outgrowth (GRIN) modulates Sprouty protein repression of mitogen-activated protein kinase (MAPK) activation by growth factor stimulation. J Biol Chem 287:13674-85
Sathyanarayana, Pradeep; Dev, Arvind; Pradeep, Anamika et al. (2012) Spry1 as a novel regulator of erythropoiesis, EPO/EPOR target, and suppressor of JAK2. Blood 119:5522-31
Collins, Sam; Waickman, Adam; Basson, Albert et al. (2012) Regulation of CD4? and CD8? effector responses by Sprouty-1. PLoS One 7:e49801
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Kuracha, Murali R; Burgess, Daniel; Siefker, Ed et al. (2011) Spry1 and Spry2 are necessary for lens vesicle separation and corneal differentiation. Invest Ophthalmol Vis Sci 52:6887-97
Michos, Odyssé; Cebrian, Cristina; Hyink, Deborah et al. (2010) Kidney development in the absence of Gdnf and Spry1 requires Fgf10. PLoS Genet 6:e1000809
Akbulut, Simge; Reddi, Alagarsamy L; Aggarwal, Priya et al. (2010) Sprouty proteins inhibit receptor-mediated activation of phosphatidylinositol-specific phospholipase C. Mol Biol Cell 21:3487-96
Shea, Kelly L; Xiang, Wanyi; LaPorta, Vincent S et al. (2010) Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration. Cell Stem Cell 6:117-29

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