Intercellular adhesion molecule-4 binds alpha(4)beta(1) and alpha(V)-family integrins through novel integrin-binding mechanisms

The LW blood group glycoprotein, ICAM-4, is a member of the intercellular a dhesion molecule (ICAM) family expressed in erythroid cells. To begin to ad dress the function of this molecule, ligands for ICAM-4 on hemopoietic and nonhemopoietic cell lines were identified. Peptide inhibition studies sugge st that adhesion of cell lines to an ICAM-4-Fc construct is mediated by an LDV-inhibitable integrin on hemopoietic cells ana an RGD-inhibitable integr in on nonhemopoietic cells,Antibody inhibition studies identified the hemop oietic integrin as alpha (4)beta (1) Antibody inhibition studies on alpha ( 4)beta (1)-negative, nonhemopoietic cell lines suggested that adhesion of t hese cells is mediated by av integrins (notably alpha (v)beta (1) and alpha (v)beta (5)). The structure of ICAM-4 modeled on the crystal structure of ICAM-2 was used to identify surface-exposed amino acid residues for site-di rected mutagenesis. Neither an unusual LETS nor an LDV motif in the first d omain of ICAM-4 was critical for integrin binding. ICAM-4 is the first ICAM family member shown to be a ligand for integrins other than those of the p q family, and the data suggest that ICAM-4 has a novel integrin-binding sit e(s). These findings suggest a role for ICAM-4 in normal erythropoiesis and may also be relevant to the adhesive interactions of sickle cells.(C) 2001 by The American Society of Hematology.