Integrin beta 3 cytoplasmic tail is necessary and sufficient for regulation of alpha 5 beta 1 phagocytosis by alpha v beta 3 and integrin-associated protein.
Using a K562 cell transfection model, we have previously described a novel relationship between the integrins alpha v beta 3 and alpha 5 beta 1. alpha v beta 3 ligation was able to inhibit alpha 5 beta 1-mediated phagocytosis without effect on alpha 5 beta 1-mediated adhesion. The alpha v beta 3-dependent inhibition apparently required a signal transduction cascade as it was reversed by inhibitors of serine/threonine kinases. Now, we have studied the mechanisms of signal transduction in this system and have found that the beta 3 cytoplasmic tail is both necessary and sufficient for initiation of the signal leading to inhibition of alpha 5 beta 1 phagocytosis. Ligation of integrin-associated protein (IAP), which has been implicated in alpha v beta 3 signal transduction, mimics the effects of alpha v beta 3 ligation only when the beta 3 integrin with an intact cytoplasmic tail is present. Although fibronectin-mediated phagocytosis requires the high affinity conformation of alpha 5 beta 1, ligation of alpha v beta 3/IAP does not prevent acquisition of this high affinity state. We conclude that alpha v beta 3/IAP ligation initates a signal transduction cascade, dependent upon the beta 3 cytoplasmic tail, which inhibits the phagocytic function of alpha 5 beta 1 at a step subsequent to modulation of integrin affinity.
Blystone
S D
SD
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Lindberg
F P
FP
LaFlamme
S E
SE
Brown
E J
EJ
D015703:Antigens, CD / Q000378:metabolism*; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D000939:Epitopes; D006801:Humans; D039661:Integrin beta3; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D004915:Leukemia, Erythroblastic, Acute; D008024:Ligands; D010446:Peptide Fragments / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016024:Receptors, Cytoadhesin / Q000378:metabolism*; D017469:Receptors, Fibronectin / Q000378:metabolism; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D000939:Epitopes; D039661:Integrin beta3; D016023:Integrins; D008024:Ligands; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016024:Receptors, Cytoadhesin; D017469:Receptors, Fibronectin; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins