Stephanie Lee
Regulation of FGF/FGFR Signaling by Glycosaminoglycans and Klotho
Mentor:  Dr. Lijuan Zhang, Department of Pathology and Immunology, Washington University School of Medicine

FGF (fibroblast growth factor) and its receptor FGFR are signaling proteins that play a role in homeostasis and animal development.  Glycosaminoglycan (GAG), a linear chain composed of repeating disaccharides, is required for FGF signaling.  Different GAGs can enhance or inhibit FGF signaling.  FGF/FGFR signals are related to different diseases such as Apert Syndrome and cancer.  They are also related to diseases where angiogenesis, osteogenesis, and tissue-injury repair are impaired.  I have learned how GAGs regulate FGF/FGFR signals by performing a routine BaF cell proliferation assay with ³H-thymidine. BaF cells, a lymphoid cell line, are dependent on cytokine Interleukin-3 (IL-3) for growth and have no response to FGF. When a FGFR is expressed in BaF3 cells, they grow in a FGF and GAG dose dependent manner in the absence of    IL-3.

The Klotho gene is known as the anti-aging gene. Research has shown that Klotho null mice show premature aging; they have shortened life spans and develop arteriosclerosis, osteoporosis, skin atrophy, infertility, and systemic aging features in organs. FGF23 has been associated with Klotho.  Mice without FGF23 have shown similar phenotypes as Klotho null mice.  Our hypothesis is that Klotho is a proteoglycan that regulates FGF23 signaling through its GAG chain. We tested this with ³⁵S metabolic labeling.  We have found that there is more ³⁵S labeling in purified Klotho protein from Klotho expressing cells than in control cells.  This preliminary data supports our hypothesis.