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  current news   Press   selected story    
     
  30 December 2009  
  Congratulations to IMCBs recent PhD graduate
 
 



PhD Gradute: Chow Soah Yee
Thesis Title: The mechanism of action of Sprouty2: Characterization of the interaction between Sprouty2 and PKCδ

Abstract
Sprouty (Spry) proteins function as inhibitors of receptor tyrosine kinase (RTK) signaling. Through their action, they play a crucial role in regulating branching morphorgenesis, development and cell migration. The best characterized function of Spry proteins is their role in inhibiting RTK-mediated ERK1/2 activation. In the past few years, studies by different groups have been carried out to elucidate the mechanisms by which Spry proteins are able to inhibit ERK activity. Most of the work performed to date concentrate on the canonical RTK-Grb2-Sos-Ras-Raf-MEK-ERK pathway. Current evidence suggests different points of action, including upstream of Ras and Raf. In this study, the question was raised as to whether Spry proteins could influence other signaling pathways, and what impact they would have. Previous studies have shown that PKCδ may have an influence on ERK1/2 activation, and that Spry proteins could affect PKCδ activity. Given these observations, the role of Spry on PKCδ signaling was examined in greater detail. The results from the study showed that Spry2 and PKCδ were able to interact specifically and directly with each other upon FGF receptor (FGFR) activation. Furthermore, the interaction prevented the phosphorylation of a PKCδ susbstrate, PKD1. The mechanics of the interaction, as identified in this study, showed that Spry2, PKCδ and PKD1 formed a trimeric complex, and in this interaction, Spry2 was able to maintain the interaction between PKCδ and PKD1, while at the same time preventing the transfer of a phosphate group from PKCδ to PKD1. This interaction also has an impact on ERK1/2 activation through PKCδ signaling, indicating that Spry2 is able to regulate a pathway separate from the canonical Ras-ERK pathway. Finally, Spry2 was shown to negatively regulate PKCδ-mediated cell invasion. This therefore has implications for the role of Spry2 in cell migration during development, and diseases such as cancer.


Figure Legend: COS1 cells were transfected with FLAG-tagged Spry2 and serum starved overnight. The cells were then either left untreated (panels e) or stimulated with bFGF (100ng/ml) (panels f) for 1h. Cells were fixed and stained with mouse anti-FLAG, rabbit anti-PKD1 and goat anti-PKCδ, followed by anti-mouse IgG (green), anti-rabbit IgG (red) and anti-goat IgG (beige) staining. Panels a, b, c and d show COS1 cells stained for PKD1 and PKCδ in the absence of Spry2, as controls.


Figure Legend: COS1 cells were transfected with FLAG-tagged Spry2 and serum starved overnight. The cells were then either left untreated (panels e) or stimulated with bFGF (100ng/ml) (panels f) for 1h. Cells were fixed and stained with mouse anti-FLAG, rabbit anti-PKD1 and goat anti-PKCδ, followed by anti-mouse IgG (green), anti-rabbit IgG (red) and anti-goat IgG (beige) staining. Panels a, b, c and d show COS1 cells stained for PKD1 and PKCδ in the absence of Spry2, as controls.

For more information on Graeme GUY's Lab, please click here.