Single-molecule binding of CD44 to fibrin versus P-selectin predicts their distinct shear-dependent interactions in cancer

Phrabha S. Raman, Christina S. Alves, Denis Wirtz, Konstantinos Konstantopoulos

Research output: Contribution to journalArticle

Abstract

P-selectin and fibrin(ogen) have pivotal roles in the hematogenous dissemination of tumor cells. CD44 variant isoforms, CD44v, have been identified as the major functional P-selectin ligands and fibrin receptors on metastatic colon carcinoma cells. The molecular recognition of CD44v by fibrin mediates firm adhesion at low shear, whereas CD44v-P-selectin binding supports transient rolling interactions at elevated shear stresses and low site densities of P-selectin. We used single-molecule force spectroscopy to provide a molecular interpretation for these two distinct adhesion events. The CD44v-P-selectin bond has a longer unstressed equilibrium lifetime, a lower reactive compliance and a higher tensile strength relative to the CD44v-fibrin bond. These intrinsic differences confer the ability to the CD44v-P-selectin pair to mediate binding at higher shear stresses. Increasing the duration of receptor-ligand contact (2-200 milliseconds) did not affect the micromechanical properties of the CD44v-P-selectin bond, but it increased the tensile strength and the depth of the free energy barrier of the CD44v-fibrin bond and decreased its reactive compliance. This bond strengthening at longer interaction times might explain why CD44v binding to immobilized fibrin occurs at low shear. Single-molecule characterization of receptor-ligand binding can predict the shear-dependent adhesive interactions between cells and substrates observed both in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)1903-1910
Number of pages8
JournalJournal of cell science
Volume124
Issue number11
DOIs
StatePublished - Jun 1 2011

Keywords

  • CD44
  • Fibrin(ogen)
  • Force spectroscopy
  • P-selectin

ASJC Scopus subject areas

  • Cell Biology

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