Research

 

Signal Transduction pathway of Allatostatin Receptor:

Allatostatins (ASTs) are neuropeptides that are originally described as inhibitors of juvenile hormone (JH) synthesis in insects. However, they also take place in muscular activity suppression in different tissues, vitellogenesis inhibition and modulate the activity of certain midgut digestive enzymes. So far, three families of allatostatins have been identified in insects (type A, B and C). ASTs are produced in Corpora Allata (CA) of arthropods and a reduction of its synthesis is required at the larval instar stages. 

Juvenile hormone is produced through the Mevalonate Pathway, in which the preliminary steps are conserved in both Arthropoda and Mammalia. Acetyl Co-A leads to production of cholesterol and some isoprenoids, which play important roles in cell signalling and carcinogenesis in Mammalia. However, in arthropods the end-product of this pathway is JH. AST peptides are known to inhibit this pathway from the first steps. 
ASTs of insects display their activity by interacting with their allatostatin receptors (AlstR). These AST receptors are classified as G protein-coupled receptors (GPCRs). 

GPCRs are membrane-bound proteins that have roles in signal transduction. They convert extrenal signal into internal signal, and, ultimately, cellular responses. GPCRs contain the biggest protein family which corresponds to 2% of human genome. They are involved in many diseases. Due to their common effects, which are known, such as regulation of hormonal and immune systems, cell proliferation, metastasis, angiogenesis etc. they are the major targets for about 60% of pharmaceuticals. 

Our group has recently focused on identification the Allatostatin-C receptor of C. morosus (CamAlstR-C). Bioinformatics modeling and docking tools are used to elucidate structural features of CamAsltR-C interaction pattern with its ligand, Allatostatin-C. This interaction was verified in vivo via atomic force microscopy (AFM) and binding force was detected in CamAlstR-C over-expressed cells. The binding pocket was predicted bioinformatically and were verified by mutating the residues at this pocket, and conducting AFM experiments for ligand binding.

Insect models are being used in a wide-range of medical and biological studies, due to their evolutionary relationships with humans. Largely known mechanisms of molecular pathways in insects may serve as model systems and as means of experimental designs. The homology in cellular mechanisms of insects can enable finding model mechanisms and making generalizations in cellular mechanisms of humans. Furthermore, functional homology studies on metabolites and hormones of insects can lead to the development of new treatment methods for human diseases. 

 

Analysis of Wnt/ß-catenin-pathway related gene expression in hepatocellular carcinoma:

Wnt/ß-katenin/TCF signal transduction pathway is the best studied among Wnt pathways. Several molecules in this pathway are associated with several different carcinomas. ß -Catenin is a key component of canonical wnt pathway which plays an important role in tumorigenesis. Nuclear accumulation of ß-catenin due to aberrant activation of Wnt pathway was reported in several tumors. 

We identifeid novel genes regulated by Wnt/B-catenin/TCF pathway identified in hepatocellular carcinoma-derived Huh7 cells over-expressing hyperactive ß-catenin (S33Y mutant). SAGE (Serial Analysis of Gene Expression) and genome wide microarray analysis were performed to compare global gene expression between Huh7 cells with high and low ß-catenin/TCF activity. We detected several molecules whose expression level have altered significantly upon ß-catenin induction. 

MGC40157, BRI3, MENA, HSF, CNN3 schema of Wnt-pathway, GPCR signaling

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