The heparanome and regulation of cell function: structures, functions and challenges

Abstract

The cell-extracellular matrix interface is a crowded space whose structure is dependent on macromolecular assemblies that are dynamic in time, molecular composition and location. Signals travel from one cell to another (or to the same cell) by the regulated assembly/disassembly of molecular complexes. These signals can evoke relatively simple biological responses such cell proliferation and migration, but once integrated, they guide cell fate in complex biological phenomena such as embryonic development and organism homeostasis. Heparan sulfate proteoglycans are ubiquitous components of this space and important actors of these processes in all tissue-organized life forms. A key feature of heparan sulfate is its size, 40 nm to 160 nm, which enables it to integrate self-assembling macromolecular structures over substantial length scales. What is the structure of heparan sulfate? Why do we think heparan sulfate is so important? How do we try to explain its activity? What do we know about its interactions? These questions together with a final look to the future are the "menu" of this review.

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

“…Increased plasma levels of FGF2 and other FGFs are found in multiple cancer types [79]. This partly reflects the increased release of FGFs as tumors invade and degrade the extracellular matrix [80], free FGF molecules acting in turn as paracrine factors. Tumor cells may also induce FGF2 release from the stromal inflammatory infiltrate [81] that may promote tumor survival via a paracrine loop of stimulation and trigger a pro-angiogenic response.…”

Roles of Heparan Sulfate Sulfation in Dentinogenesis

“…HS traps many different proteins on the cell surface and basement membrane and regulates their functions (2,3). There is considerable interest in the structural variability generated by a series of modifications within HS, which are responsible for the binding and regulation of specific HS-interacting proteins (4,5). Such HS modifications, in particular in the form of its sulfation patterns, result in structural and functional heterogeneity, which are controlled in a tissue-specific and developmental manner (6).…”

Influence of Heparin Mimetics on Assembly of the FGF·FGFR4 Signaling Complex

“…All FGFs interact with heparan sulfate glycosaminoglycans (HSGAGs) 3 (20). The HSGAG-binding site of FGFs is composed of the ␤1-␤2 loop and the region encompassing ␤10 through ␤12 (10,(21)(22)(23)(24)(25).…”