Distinct ligand-binding modes for integrin alpha(v)beta(3)-mediated adhesion to fibronectin versus vitronectin.
Cell surface integrins can adopt distinct conformations in response to ligand binding and intracellular signals. Several integrins including alpha(v)beta(3) can bind to multiple ligands. The binding of alpha(v)beta(3) to fibronectin and vitronectin was used as a model to determine whether the same or distinct forms of the receptor were utilized in strong binding to the two different ligands. A spinning-disc device was used to measure the relative strength of the alpha(v)beta(3)-ligand bonds. The initial binding reaction for both ligands occurred in the absence of metabolic energy and resulted in a strong adhesion to fibronectin but a weak adhesion to vitronectin. Increases in the strength of the alpha(v)beta(3)-vitronectin bond required phosphorylation of the beta(3) cytoplasmic domain, intracellular signals, and the binding of cytoskeletal proteins to cytoplasmic domains of beta(3) controlled by Tyr-747 and Tyr-759. In contrast, alpha(v)beta(3)-mediated adhesion to fibronectin was unaffected by phorbol 12-myristate 13-acetate, mutations of Tyr-747 and Tyr-759 to phenylalanine, or availability of metabolic energy. This suggests that strong adhesion to fibronectin used the initial binding conformation, whereas strong binding to vitronectin required signaling-induced changes in the conformation of alpha(v)beta(3).
Boettiger
D
D
Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. boettige@mail.med.upenn.edu
Lynch
L
L
Blystone
S
S
Huber
F
F
D000199:Actins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D008024:Ligands; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019096:Vitronectin / Q000378:metabolism*
D000199:Actins; D005353:Fibronectins; D008024:Ligands; D019030:Receptors, Vitronectin; D019096:Vitronectin