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  current news   Press   selected story    
     
  4 March 2010  
 

Congratulations to IMCB’s recent PhD graduates

 
 



(To view more about each student's thesis, please click on his/her name in the image above)

PhD Gradute: Goh Choon Peng
Thesis Title: DNA binding motifs, nuclear import & export signals regulate the subcellular localization of Slug.

Abstract
Epithelial-mesenchymal transition (EMT) is a process characterized by the loss of cell-cell adhesion and apical-basal polarity of epithelial cells to acquire migratory and mesenchymal properties. The Snail superfamily members SNAI1 and SNAI2 (Slug) have emerged as important regulators of EMT, both in development and cancer. They share a common structural organization with a highly conserved C-terminal region containing four to six C2H2-type zinc fingers that bind consensus E2-box type DNA elements and a divergent N-terminal region with a conserved SNAG domain that is important for repressor activity. In the central region, SNAI1 contains a nuclear export signal (NES), whereas SNAI2 carries a Slug domain of unknown function. Regulation of the subcellular distribution has been characterized for SNAI1, but not for SNAI2. SNAI1 carries a basic cluster NLS proximal to the first zinc finger domain. Cytosolic localization of SNAI1 depends on CRM-1-dependent nuclear export, which is regulated by phosphorylation of a Ser-rich sequence adjacent to a NES. In the present study I identified and characterized signals and domains in SNAI2 that are involved in regulating its subcellular distribution and DNA binding. SNAI2 contains two NLSs and one NES. The NLSs interact with multiple importins. A combination of individual zinc finger domains is required for DNA binding. Besides nuclear import and export, DNA binding contributes to the subcellular distribution of SNAI2. This work thus establishes similarities and differences in the regulation of the subcellular distribution of SNAI2 as compared to SNAI1, which are of relevance for the regulation of the trancriptional repressor function of these proteins.

 
 


 
 

Figure Legend: Sequence comparison of various members of the Snail superfamily.

a) Overall structure of Snail superfamily members including the relative positions of the SNAG domain, zinc fingers (IV), as well as the Scratch- and Slug-specific boxes. b) Consensus sequences of the different zinc fingers for Snail (Sna; light purple), Scratch (Scrt; green) and the whole Snail superfamily (dark purple). c, d) Sequence comparison of the Slug and Scratch specific domains respectively across various organisms. (Dm, Drosophila melanogaster; Dr, Danio rerio; Gg, Gallus gallus; Hs, Homo sapiens; Mm, Mus musculus; Xl, Xenopus laevis) e) Sequences of the SNAG domain present in representative members of the three big groups of bilateralians. (Bf, Brachiostoma floridae; Lv, Lytechinus variegatus; Pv, Patella vulgate) The zinc-finger region and the SNAG domain have been shown to be fundamental for protein function, while the domains specific for Slug and Scratch allow the classification of these members into their assigned subfamilies. (Adapted from Nature Review Molecular Cell Biology 2002; 3: 455-466)

For more information on Walter Hunziker's Lab, please click here.

 

 
 


PhD Gradute: Ong Yan Shan
Thesis Title: p125A, a COPII interacting protein

Abstract
Coat protein complex II (COPII) coated vesicles/carriers mediate the export of proteins from the ER via specialized domains known as the ER exit sites (ERES). p125A is a protein of 125 kDa that interacts with Sec23A, a component of the COPII coat. It was found to participate in the organization of ER exit sites (Tani et al., 1999; Shimoi et al., 2005). In this current study, using GST-pull down and mass spectrometry analysis, p125A is also identified as one of the proteins interacting with Sec31A, another member of the COPII coat. Deletion mutant analysis of p125A narrowed its Sec31A-interacting domain to be within residues 260-600. Binding of p125A to Sec31A is direct and independent of the interactions with Sec23A. Gel filtration and immune-depletion studies suggest that p125A exists as a ternary complex with the Sec13/Sec31 heterotetramer in the cytosol. Knockdown of p125A using siRNA shows that the Golgi apparatus is fragmented and that the export of proteins from the ER is delayed in p125A depleted cells suggesting that p125A is essential for efficient protein trafficking in the early secretory pathway. p125A silencing also caused a decrease in membrane association for Sec13 and Sec31A, but not Sec23A. Knockdown of Sec31A results in a re-distribution of p125A to the cytosol, indicating that Sec31A is important for the association of p125A to the membrane. In summary, the results suggest that p125A is involved in stabilizing the association of the Sec13/Sec31 heterotetramer to the ERES, which is essential for efficient ER export.

 
 


 
 

Figure Legend: Schematic illustration of p125As interaction with Sec13/Sec31 and Sec23/Sec24 at the ERES membrane.
p125A exists as a ternary complex with Sec13/Sec31 in the cytosol, prior to its recruitment to the membrane.
Activated Sar1 associates to the membrane and recruits Sec23/Sec24, followed by p125A-Sec13/Sec31
complex.

For more information on Wanjin HONG's Lab, please click here.