The fibroblast growth factor (FGF) signaling system is a ubiquitous cellular sensor of local environmental changes and mediator of cell-to-cell communication with broad roles in development and in the adulthood. A concerted interplay of three essential components, including FGFs, their high-affinity partners—FGF receptors (FGFRs), and highly sulfated polysaccharides—heparin/heparan sulfate (HS) proteoglycans (HSPGs), mediates FGF signaling resulting in the functional versatility of developmental and physiological processes. The multitude of biological effects of FGFs and the many signaling pathways activated by this family of ligands imply that FGF signaling must be tightly regulated regarding timing, duration and spread of the signal. In fact, spatial and temporal expression of FGFs, FGFRs and HSPGs, together with tissue-specific dependent alternative splicing, are the major determinants of FGF binding specificity, duration and the extent of signaling. The regulation is further achieved by both positive and negative feedback loops in the extracellular space and within the cell. Indeed loss of these autoinhibitory mechanisms is often the culprit of human pathologies. Herein, I describe two novel autoregulatory mechanisms by which FGFs and FGFRs can maintain and modulate the delicate balance necessary for proper FGF signaling. Specifically, I show that homodimerization of FGF9 and FGF20 autoinhibits signaling activity of these ligands by suppressing both receptor binding and HS-dependent diffusion in the extracellular matrix (ECM). Also I address the role of the acid box (AB) linker region in FGFR3c autoinhibition. I show that the alternatively spliced AB of FGFR3c plays a focal role in FGFR autoinhibition (1) by blocking the heparin-binding site (HBS) of FGFR in cis; (2) by occluding the HBS of the ligand in trans and (3) by generating futile/signaling-incompetent FGF/FGFR complexes.
|Commitee:||Basilico, Claudio, Cowburn, David, Kong, Xiangpeng, Nikolov, Dimitar, Tjandra, Nico|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 70/12, Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology|
|Keywords:||Autoinhibition, FGFR, Fibroblast growth factor, Homodimerization, Regulation|
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