Abstract

Fibroblast growth factors (GFs) play a fundamental role in development, and aberrant expression of these proteins is central to the progression of several disease states. Therefore, FGF-mediated signaling is a desirable target for therapeutic intervention. For example, enhancing FGF signaling may facilitate wound repair, whereas inhibiting FGF activity may help controlling cancer and inflammatory diseases. FGFs bind to extracellular heparin-like glycosaminoglycans (HLGAGs) and the HLGAG-FGF complex binding to its specific cognate receptor (FGFR) at the cell surface leads to FGFR oligomerization, intracellular signal transduction, and ultimately, initiation of cell proliferation or differentiation. Focusing on FGF-2 as a model system, the overall goal of this grant is to elucidate the molecular mechanism by which HLGAGs regulate FGF-2 biological activity. Our preliminary investigations suggest that FGF-2 has a tendency to self-associate and this FGF-2 oligomerization is modulated by the length and sequences of HLGAGs. Based on our preliminary findings, we hypothesize that the differential biological response of particular HLGAG sequences can be rationalized in the context of different FGF-2 dimerization/oligomerization modes they induce and stabilize. In this case, the differences between 'active' and 'inactive' HLGAGs are manifested in the mode of FGF-2 oligomerization they induce. Our preliminary studies provide a framework for an in-depth analysis of the proposed hypothesis, yielding valuable information on FGF-2 oligomerization and the role of HLGAGs in modulating FGF-2 oligomerization and how this impinges on the biological activity of FGF-2. Insight into the molecular interactions of the HLGAG-FGF system obtained from these studies will help provide leverage for new approaches to therapeutic control of FGF-mediated signal transduction in pathological situations. Further, these studies will provide a framework to investigate numerous other HLGAG-binding growth factors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059966-03
Application #
6389868
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Link, Rebecca P
Project Start
1999-06-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
3
Fiscal Year
2001
Total Cost
$236,447
Indirect Cost

  Institution

Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139

  Publications

Guerrini, Marco; Zhang, Zhenqing; Shriver, Zachary et al. (2009) Orthogonal analytical approaches to detect potential contaminants in heparin. Proc Natl Acad Sci U S A 106:16956-61
Guglier, Sara; Hricovini, Milos; Raman, Rahul et al. (2008) Minimum FGF2 binding structural requirements of heparin and heparan sulfate oligosaccharides as determined by NMR spectroscopy. Biochemistry 47:13862-9
Guerrini, Marco; Hricovini, Milos; Torri, Giangiacomo (2007) Interaction of heparins with fibroblast growth factors: conformational aspects. Curr Pharm Des 13:2045-56
Raman, Rahul; Sasisekharan, V; Sasisekharan, Ram (2005) Structural insights into biological roles of protein-glycosaminoglycan interactions. Chem Biol 12:267-77
Berry, David; Ren, JingMei; Kwan, Chi-Pong et al. (2005) Dimeric fibroblast growth factor-2 enhances functional recovery after focal cerebral ischemia. Restor Neurol Neurosci 23:251-6
Berry, David; Shriver, Zachary; Venkataraman, Ganesh et al. (2004) Quantitative assessment of FGF regulation by cell surface heparan sulfates. Biochem Biophys Res Commun 314:994-1000
Berry, David; Lynn, David M; Sasisekharan, Ram et al. (2004) Poly(beta-amino ester)s promote cellular uptake of heparin and cancer cell death. Chem Biol 11:487-98
Berry, David; Shriver, Zachary; Natke, Barbara et al. (2003) Heparan sulphate glycosaminoglycans derived from endothelial cells and smooth muscle cells differentially modulate fibroblast growth factor-2 biological activity through fibroblast growth factor receptor-1. Biochem J 373:241-9
Raman, Rahul; Venkataraman, Ganesh; Ernst, Steffen et al. (2003) Structural specificity of heparin binding in the fibroblast growth factor family of proteins. Proc Natl Acad Sci U S A 100:2357-62
Sundaram, Mallik; Qi, Yiwei; Shriver, Zachary et al. (2003) Rational design of low-molecular weight heparins with improved in vivo activity. Proc Natl Acad Sci U S A 100:651-6

Showing the most recent 10 out of 16 publications