Heparan sulfate proteoglycans mediate factor XIIa binding to the cell surface

J Biol Chem. 2015 Mar 13;290(11):7027-39. doi: 10.1074/jbc.M114.606343. Epub 2015 Jan 14.


Hageman factor (FXIIa) initiates the intrinsic coagulation pathway and triggers the kallikrein-kinin and the complement systems. In addition, it functions as a growth factor by expressing promitogenic activities toward several cell types. FXIIa binds to the cell surface via a number of structurally unrelated surface receptors; however, the underlying mechanisms are not yet fully understood. Here, we demonstrate that FXIIa utilizes cell membrane-bound glycosaminoglycans to interact with the cell surface of human lung fibroblasts (HLF). The combination of enzymatic, inhibitory, and overexpression approaches identified a heparan sulfate (HS) component of proteoglycans as an important determinant of the FXIIa binding capacity of HLF. Moreover, cell-free assays and competition experiments revealed preferential binding of FXIIa to HS and heparin over dextran sulfate, dermatan sulfate, and chondroitin sulfate A and C. Finally, we demonstrate that fibroblasts isolated from the lungs of the patients suffering from idiopathic pulmonary fibrosis (IPF) exhibit enhanced FXIIa binding capacity. Increased sulfation of HS resulting from elevated HS 6-O-sulfotransferase-1 expression in IPF HLF accounted, in part, for this phenomenon. Application of RNA interference technology and inhibitors of intracellular sulfation revealed the cooperative action of cell surface-associated HS and urokinase-type plasminogen activator receptor in the accumulation of FXIIa on the cell surface of IPF HLF. Moreover, FXIIa stimulated IPF HLF migration, which was abrogated by pretreatment of cells with heparinase I. Collectively, our study uncovers a novel role of HS-type glycosaminoglycans in a local accumulation of FXIIa on the cell membrane. The enhanced association of FXIIa with IPF HLF suggests its contribution to fibrogenesis.

Keywords: Cell Biology; Factor XIIa; Glycosaminoglycan; Heparan Sulfate; Proteoglycan; Pulmonary Fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Factor XIIa / analysis
  • Factor XIIa / metabolism*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Heparan Sulfate Proteoglycans / analysis
  • Heparan Sulfate Proteoglycans / metabolism*
  • Humans
  • Lung / metabolism
  • Lung / pathology*
  • Protein Binding
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology*


  • Heparan Sulfate Proteoglycans
  • Factor XIIa