Fibroblast growth factors (FGFs) regulate a range of physiological and pathological processes. They promote growth and differentiation of cell types found in tissues derived from all three embryonic germ layers and mediate aspects of cell embryonic development (e.g., muscle and nerve development) angiogenesis. cell motility, and also function significantly in regulating development of various tumor types. FGFs elicit cellular responses by binding and activating cell surface FGF receptor tyrosine kinases (FGFRs 1-4). Specific signal transduction pathways are initiated upon receptor activation leading to a variety of cellular responses. Cell surface heparan sulfate proteoglycans (HSPGs facilitate FGF/FGFR interactions. Several classes of HSPG exist; two of these are the syndecans (Synds 1-4), integral membrane HSPGs, and lipid-linked HSPGs such as cerebroglycan (CBG). Both forms are the focus of the experiments proposed here. Both forms bind FGF, but the different means of anchoring to the cell surface suggest that different responses to FGFs are regulated by which form mediates FGF/FGFr interactions. The goal of this research is to clarify the role that HSPGs play in mediating FGF signaling by asking questions of a cell expressing a single HSPG along with a single FGF receptor type.
The specific aims are 1) determine if soluble Synd1 or CBG differ in their ability to mediate FGF signaling in FGFR positive/HSPG negative cells; 2) determine if cell surface anchored Synd1 or CBG co- expressed with a single type of FGFR in a lymphoid cell line normally devoid of these molecules differ in their ability to promote FGF binding to and/or activation of the FGFR: 3) assess the effects of modulating cell surface levels of Synd1 or CBG in inhibiting FGF binding to and/or activation of the FGFR in FGF responsive cells and 4) examine the ability of Synd1 and CBG to mediate activation of different FGF/FGFR signal transduction pathways in FGF responsive cells.
| Home, Pratik; Kumar, Ram Parikshan; Ganguly, Avishek et al. (2017) Genetic redundancy of GATA factors in the extraembryonic trophoblast lineage ensures the progression of preimplantation and postimplantation mammalian development. Development 144:876-888 |
