Histidine-rich glycoprotein blocks collagen-binding integrins and adhesion of endothelial cells through low-affinity interaction with α2 integrin

Matrix Biol. 2015 Oct:48:89-99. doi: 10.1016/j.matbio.2015.06.002. Epub 2015 Jun 5.


The plasma protein histidine-rich glycoprotein (HRG) affects the morphology and function of both endothelial cells (ECs) and monocytes/macrophages in cancer. Here, we examined the mechanism of action of HRG's effect on ECs. HRG suppressed adhesion, spreading and migration of ECs specifically on collagen I (COL I) whereas ECs seeded on other extracellular matrix proteins were insensitive to HRG. HRG did not bind specifically to COL I or to the α-integrin binding site on collagen, GFOGER. Furthermore, HRG's inhibition of EC adhesion was not dependent upon heparan sulfate (HS) moieties as heparitinase-treated ECs remained sensitive to HRG. C2C12 cells expressing α2 integrin, the major collagen-binding α-integrin subunit in ECs, showed increased binding of HRG compared with wild type C2C12 cells lacking the α2 subunit. Recombinant α2 I-domain protein bound HRG and to a higher extent when in active conformation. However, the α2 I-domain bound weakly to HRG compared with COL I and the purified α2β1 ectodomain complex failed to retain HRG. We conclude that HRG binds to α2 integrin through low-affinity interactions in a HS-independent manner, thereby blocking EC-adhesion to COL I.

Keywords: Adhesion; Collagen; Endothelial cells; HRG; Integrin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Line
  • Chemotaxis / drug effects
  • Female
  • Gene Expression
  • Heparitin Sulfate / chemistry*
  • Heparitin Sulfate / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Integrin alpha2beta1 / chemistry*
  • Integrin alpha2beta1 / genetics
  • Integrin alpha2beta1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myoblasts / cytology
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Subunits / chemistry*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Vascular Endothelial Growth Factor A / pharmacology


  • Integrin alpha2beta1
  • Protein Subunits
  • Proteins
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor A
  • histidine-rich proteins
  • vascular endothelial growth factor A, mouse
  • Heparitin Sulfate

Associated data

  • GEO/GSE66768