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 adhesion molecule (ICAM) family expressed in erythroid cells. To begin to address the function of this molecule, ligands for ICAM-4 on hemopoietic and nonhemopoietic cell lines were identified. Peptide inhibition studies suggest that adhesion of cell lines to an ICAM-4-Fc construct is mediated by an LDV-inhibitable integrin on hemopoietic cells and an RGD-inhibitable integrin on nonhemopoietic cells. Antibody inhibition studies identified the hemopoietic integrin as alpha(4)beta(1.) Antibody inhibition studies on alpha(4)beta(1)-negative, nonhemopoietic cell lines suggested that adhesion of these cells is mediated by alpha(V) 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-directed mutagenesis. Neither an unusual LETS nor an LDV motif in the first domain 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 beta(2) family, and the data suggest that ICAM-4 has a novel integrin-binding site(s). These findings suggest a role for ICAM-4 in normal erythropoiesis and may also be relevant to the adhesive interactions of sickle cells.
Spring
F A
FA
Bristol Institute for Transfusion Sciences, United Kingdom. fran.spring@nbs.nhs.uk
Parsons
S F
SF
Ortlepp
S
S
Olsson
M L
ML
Sessions
R
R
Brady
R L
RL
Anstee
D J
DJ
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry; D001665:Binding Sites; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004920:Erythropoiesis; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000166:cytology; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D019030:Receptors, Vitronectin; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017385:Sequence Homology
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; C065289:ICAM2 protein, human; C095100:ICAM4 protein, human; D039041:Integrin alpha4beta1; D016023:Integrins; D008024:Ligands; D016201:Receptors, Lymphocyte Homing; D019030:Receptors, Vitronectin; D011993:Recombinant Fusion Proteins; C064660:integrin alphaVbeta5; C094340:integrin alphavbeta1