Embryo implantation involves complex, programmed interactions among cell surface, extracellular matrix components and growth factor/growth factor receptor-driven processes. Studies from various labs, including the PI's, indicate that heparan sulfate (HS) proteoglycans and HS-binding proteins play key roles at multiple steps of implantation. Important HS-binding proteins include growth factors such as heparin-binding, EGF-like growth factor (HB-EGF), hepatocyte growth factor (HGF) and fibroblast growth factor-2 (FGF-2) as well as HS/heparin interacting protein (HIP/L29), a multifunctional protein identified in the PI's lab as a cell surface component of many epithelial cells and cell lines. HIP/L29 supports blastocyst and cell attachment as well as modulates aspects of the blood coagulation cascade. HIP/29 is highly expressed by uterine epithelia throughout the uterine cycle in both mice and humans. HS-binding growth factors can be released from sites of deposition in the extracellular matrix by the action of heparanase. In this regard, a peptide motif of HIP/L29 has been shown to inhibit heparanase, suggesting that HIP/L29 modulates heparanase-dependent growth factor release. Consistent with this proposal are our recent observations that HIP/L29 or peptides derived from HIP/L29 modulate growth factor activities and cell growth in several systems. Thus, HIP/L29 may play multiple roles in uterine tissues and the fetal-maternal interface including regulation of hemostasis, promotion of cell adhesion and modulation of growth factor activity. In this proposal, we will extend our studies of HIP/L29 function in uterine physiology and implantation using HIP/L29-specific probes, recombinant proteins and molecular genetic approaches in human cell model systems and transgenic mice. We will determine if HIP/L29 modulates the activities of FGF-2, HGF and HB-EGF on cell growth and migration in vitro and to what extent this involves actions at the level of competition for HS binding versus inhibition of heparanase-dependent growth factor mobilization. In addition, we will examine the role(s) that HIP/L29 plays in vivo using transgenic mouse models.
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