GDNF Receptors: Veterans and Novices

1. LITERATURE REVIEW .........................................................................................1 1.1. Growth factors and neurotrophic factors ..............................................................1 1.2. GDNF family ligands ...........................................................................................5 GFLs structure and receptor complexes ..............................................................5 Biological effects and therapeutic potential of GFLs ..........................................6 1.3. GFLs receptors: GFR /RET receptor complex ....................................................8 Mechanism of RET activation ..............................................................................8 RET kinase domain .............................................................................................11 Downstream signaling ........................................................................................13 Lipid rafts and their role in GDNF signaling ....................................................14 RET as a dependence receptor ...........................................................................15 1.4. RET in disease ....................................................................................................15 1.5. RET-independent GFLs signaling ......................................................................17 Evidence for RET-independent GFLs signaling .................................................17 Neural cell adhesion molecule is an alternative GFL receptor .........................18 1.6. Heparan sulfate proteoglycans............................................................................20 Syndecans ...........................................................................................................23 Role of HSPGs in GDNF-signaling? .................................................................24 Syndecans signaling ...........................................................................................25 Syndecans in disease ..........................................................................................26 2. AIMS OF THE STUDY ..........................................................................................28 3. MATERIALS AND METHODS ............................................................................29 4. RESULTS AND DISCUSSION ..............................................................................30 4.1. HSPG syndecan-3 is a novel GFL receptor ........................................................30 4.2. The structure of GDNF-GFR 1 complex ..........................................................36 4.3. The putative structure of GDNF-GFR 1-RET complex ....................................39 5. SUMMARY AND CONCLUSIONS .......................................................................42 6. ACKNOWLEDGEMENTS .....................................................................................43 7. REFERENCES .........................................................................................................45